MENU
The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.
More About: ESP | OUR CONTENT | THIS WEBSITE | WHAT'S NEW | WHAT'S HOT
ESP: PubMed Auto Bibliography 10 Dec 2023 at 01:56 Created:
Topologically Associating Domains
"Recent studies have shown that chromosomes in a range of organisms are compartmentalized in different types of chromatin domains. In mammals, chromosomes form compartments that are composed of smaller Topologically Associating Domains (TADs). TADs are thought to represent functional domains of gene regulation but much is still unknown about the mechanisms of their formation and how they exert their regulatory effect on embedded genes. Further, similar domains have been detected in other organisms, including flies, worms, fungi and bacteria. Although in all these cases these domains appear similar as detected by 3C-based methods, their biology appears to be quite distinct with differences in the protein complexes involved in their formation and differences in their internal organization." QUOTE FROM: Dekker Job and Heard Edith (2015), Structural and functional diversity of Topologically Associating Domains, FEBS Letters, 589, doi: 10.1016/j.febslet.2015.08.044
Created with PubMed® Query: ( "Topologically Associating Domains" OR "Topologically Associating Domain" ) NOT pmcbook NOT ispreviousversion
Citations The Papers (from PubMed®)
RevDate: 2023-12-07
Evolutionary insights into the organization of chromatin structure and landscape of transcriptional regulation in plants.
Trends in plant science pii:S1360-1385(23)00368-0 [Epub ahead of print].
Development of complex traits necessitates the functioning and coordination of intricate regulatory networks involving multiple genes. Understanding 3D chromatin structure can facilitate insight into the regulation of gene expression by regulatory elements. This potential, of visualizing the role of chromatin organization in the evolution and function of regulatory elements, remains largely unexplored. Here, we describe new perspectives that arise from the dual considerations of sequence variation of regulatory elements and chromatin structure, with a special focus on whole-genome doubling or polyploidy. We underscore the significance of hierarchical chromatin organization in gene regulation during evolution. In addition, we describe strategies for exploring chromatin organization in future investigations of regulatory evolution in plants, enabling insights into the evolutionary influence of regulatory elements on gene expression and, hence, phenotypes.
Additional Links: PMID-38061928
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38061928,
year = {2023},
author = {Long, Y and Wendel, JF and Zhang, X and Wang, M},
title = {Evolutionary insights into the organization of chromatin structure and landscape of transcriptional regulation in plants.},
journal = {Trends in plant science},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tplants.2023.11.009},
pmid = {38061928},
issn = {1878-4372},
abstract = {Development of complex traits necessitates the functioning and coordination of intricate regulatory networks involving multiple genes. Understanding 3D chromatin structure can facilitate insight into the regulation of gene expression by regulatory elements. This potential, of visualizing the role of chromatin organization in the evolution and function of regulatory elements, remains largely unexplored. Here, we describe new perspectives that arise from the dual considerations of sequence variation of regulatory elements and chromatin structure, with a special focus on whole-genome doubling or polyploidy. We underscore the significance of hierarchical chromatin organization in gene regulation during evolution. In addition, we describe strategies for exploring chromatin organization in future investigations of regulatory evolution in plants, enabling insights into the evolutionary influence of regulatory elements on gene expression and, hence, phenotypes.},
}
RevDate: 2023-12-04
Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression.
Nature genetics [Epub ahead of print].
Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.
Additional Links: PMID-38049665
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38049665,
year = {2023},
author = {Leeman-Neill, RJ and Song, D and Bizarro, J and Wacheul, L and Rothschild, G and Singh, S and Yang, Y and Sarode, AY and Gollapalli, K and Wu, L and Zhang, W and Chen, Y and Lauring, MC and Whisenant, DE and Bhavsar, S and Lim, J and Swerdlow, SH and Bhagat, G and Zhao, Q and Berchowitz, LE and Lafontaine, DLJ and Wang, J and Basu, U},
title = {Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38049665},
issn = {1546-1718},
support = {R01AI134988//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; RO1AI143897//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01AI099195//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; DOD W81XWH-18-1-0394//U.S. Department of Defense (United States Department of Defense)/ ; GM124633//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32CA265828//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; },
abstract = {Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.},
}
RevDate: 2023-11-29
Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.
Molecular cancer, 22(1):190.
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.
METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.
RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).
CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.
Additional Links: PMID-38017545
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38017545,
year = {2023},
author = {Llinàs-Arias, P and Ensenyat-Mendez, M and Íñiguez-Muñoz, S and Orozco, JIJ and Valdez, B and Salomon, MP and Matsuba, C and Solivellas-Pieras, M and Bedoya-López, AF and Sesé, B and Mezger, A and Ormestad, M and Unzueta, F and Strand, SH and Boiko, AD and Hwang, ES and Cortés, J and DiNome, ML and Esteller, M and Lupien, M and Marzese, DM},
title = {Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.},
journal = {Molecular cancer},
volume = {22},
number = {1},
pages = {190},
pmid = {38017545},
issn = {1476-4598},
support = {CD22/00026//Instituto de Salud Carlos III/ ; CPII22/00004//Instituto de Salud Carlos III/ ; IMP21/10//IDISBA - Impetus Call/ ; Margalida Comas//Govern de les Illes Balears/ ; },
abstract = {BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.
METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.
RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).
CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.},
}
RevDate: 2023-11-28
Hi-C sequencing unravels dynamic three-dimensional chromatin interactions in muntjac lineage: insights from chromosome fusions in Fea's muntjac genome.
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 31(4):34.
Eukaryotes have varying numbers and structures of characteristic chromosomes across lineages or species. The evolutionary trajectory of species may have been affected by spontaneous genome rearrangements. Chromosome fusion drastically alters karyotypes. However, the mechanisms and consequences of chromosome fusions, particularly in muntjac species, are poorly understood. Recent research-based advancements in three-dimensional (3D) genomics, particularly high-throughput chromatin conformation capture (Hi-C) sequencing, have allowed for the identification of chromosome fusions and provided mechanistic insights into three muntjac species: Muntiacus muntjak, M. reevesi, and M. crinifrons. This study aimed to uncover potential genome rearrangement patterns in the threatened species Fea's muntjac (Muntiacus feae), which have not been previously examined for such characteristics. Deep Hi-C sequencing (31.42 × coverage) was performed to reveal the 3D chromatin architecture of the Fea's muntjac genome. Patterns of repeated chromosome fusions that were potentially mediated by high-abundance transposable elements were identified. Comparative Hi-C maps demonstrated linkage homology between the sex chromosomes in Fea's muntjac and autosomes in M. reevesi, indicating that fusions may have played a crucial role in the evolution of the sex chromosomes of the lineage. The species-level dynamics of topologically associated domains (TADs) suggest that TAD organization could be altered by differential chromosome interactions owing to repeated chromosome fusions. However, research on the effect of TADs on muntjac genome evolution is insufficient. This study generated Hi-C data for the Fea's muntjac, providing a genomic resource for future investigations of the evolutionary patterns of chromatin conformation at the chromosomal level.
Additional Links: PMID-38017297
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38017297,
year = {2023},
author = {Jehangir, M and Ahmad, SF and Singchat, W and Panthum, T and Thong, T and Aramsirirujiwet, P and Lisachov, A and Muangmai, N and Han, K and Koga, A and Duengkae, P and Srikulnath, K},
title = {Hi-C sequencing unravels dynamic three-dimensional chromatin interactions in muntjac lineage: insights from chromosome fusions in Fea's muntjac genome.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {31},
number = {4},
pages = {34},
pmid = {38017297},
issn = {1573-6849},
support = {P-20-52605//National Science and Technology Development Agency (NSTDA)/ ; },
abstract = {Eukaryotes have varying numbers and structures of characteristic chromosomes across lineages or species. The evolutionary trajectory of species may have been affected by spontaneous genome rearrangements. Chromosome fusion drastically alters karyotypes. However, the mechanisms and consequences of chromosome fusions, particularly in muntjac species, are poorly understood. Recent research-based advancements in three-dimensional (3D) genomics, particularly high-throughput chromatin conformation capture (Hi-C) sequencing, have allowed for the identification of chromosome fusions and provided mechanistic insights into three muntjac species: Muntiacus muntjak, M. reevesi, and M. crinifrons. This study aimed to uncover potential genome rearrangement patterns in the threatened species Fea's muntjac (Muntiacus feae), which have not been previously examined for such characteristics. Deep Hi-C sequencing (31.42 × coverage) was performed to reveal the 3D chromatin architecture of the Fea's muntjac genome. Patterns of repeated chromosome fusions that were potentially mediated by high-abundance transposable elements were identified. Comparative Hi-C maps demonstrated linkage homology between the sex chromosomes in Fea's muntjac and autosomes in M. reevesi, indicating that fusions may have played a crucial role in the evolution of the sex chromosomes of the lineage. The species-level dynamics of topologically associated domains (TADs) suggest that TAD organization could be altered by differential chromosome interactions owing to repeated chromosome fusions. However, research on the effect of TADs on muntjac genome evolution is insufficient. This study generated Hi-C data for the Fea's muntjac, providing a genomic resource for future investigations of the evolutionary patterns of chromatin conformation at the chromosomal level.},
}
RevDate: 2023-11-28
Genome folding principles revealed in condensin-depleted mitotic chromosomes.
bioRxiv : the preprint server for biology pii:2023.11.09.566494.
During mitosis, condensin activity interferes with interphase chromatin structures. Here, we generated condensin-free mitotic chromosomes to investigate genome folding principles. Co- depletion of condensin I and II, but neither alone, triggered mitotic chromosome compartmentalization in ways that differ from interphase. Two distinct euchromatic compartments, indistinguishable in interphase, rapidly emerged upon condensin loss with different interaction preferences and dependence on H3K27ac. Constitutive heterochromatin gradually self-aggregated and co-compartmentalized with the facultative heterochromatin, contrasting with their separation during interphase. While topologically associating domains (TADs) and CTCF/cohesin mediated structural loops remained undetectable, cis-regulatory element contacts became apparent, providing an explanation for their quick re-establishment during mitotic exit. HP1 proteins, which are thought to partition constitutive heterochromatin, were absent from mitotic chromosomes, suggesting, surprisingly, that constitutive heterochromatin can self-aggregate without HP1. Indeed, in cells traversing from M- to G1-phase in the combined absence of HP1α, HP1Π and HP1γ, re-established constitutive heterochromatin compartments normally. In sum, "clean-slate" condensin-deficient mitotic chromosomes illuminate mechanisms of genome compartmentalization not revealed in interphase cells.
Additional Links: PMID-38014261
Full Text:
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38014261,
year = {2023},
author = {Zhao, H and Lin, Y and Lin, E and Liu, F and Shu, L and Jing, D and Wang, B and Wang, M and Shan, F and Zhang, L and Lam, JC and Midla, SC and Giardine, BM and Keller, CA and Hardison, RC and Blobel, GA and Zhang, H},
title = {Genome folding principles revealed in condensin-depleted mitotic chromosomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.11.09.566494},
pmid = {38014261},
abstract = {During mitosis, condensin activity interferes with interphase chromatin structures. Here, we generated condensin-free mitotic chromosomes to investigate genome folding principles. Co- depletion of condensin I and II, but neither alone, triggered mitotic chromosome compartmentalization in ways that differ from interphase. Two distinct euchromatic compartments, indistinguishable in interphase, rapidly emerged upon condensin loss with different interaction preferences and dependence on H3K27ac. Constitutive heterochromatin gradually self-aggregated and co-compartmentalized with the facultative heterochromatin, contrasting with their separation during interphase. While topologically associating domains (TADs) and CTCF/cohesin mediated structural loops remained undetectable, cis-regulatory element contacts became apparent, providing an explanation for their quick re-establishment during mitotic exit. HP1 proteins, which are thought to partition constitutive heterochromatin, were absent from mitotic chromosomes, suggesting, surprisingly, that constitutive heterochromatin can self-aggregate without HP1. Indeed, in cells traversing from M- to G1-phase in the combined absence of HP1α, HP1Π and HP1γ, re-established constitutive heterochromatin compartments normally. In sum, "clean-slate" condensin-deficient mitotic chromosomes illuminate mechanisms of genome compartmentalization not revealed in interphase cells.},
}
RevDate: 2023-11-28
Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers.
Molecular oncology [Epub ahead of print].
HPV infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome-wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and TADs. HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long-range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi-C and 4C-seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~500kb apart), leading to allele-specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.
Additional Links: PMID-38013620
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid38013620,
year = {2023},
author = {Singh, AK and Walavalkar, K and Tavernari, D and Ciriello, G and Notani, D and Sabarinathan, R},
title = {Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers.},
journal = {Molecular oncology},
volume = {},
number = {},
pages = {},
doi = {10.1002/1878-0261.13559},
pmid = {38013620},
issn = {1878-0261},
abstract = {HPV infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome-wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and TADs. HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long-range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi-C and 4C-seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~500kb apart), leading to allele-specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.},
}
RevDate: 2023-11-17
Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells.
Epigenetics, 18(1):2276425.
An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2.Abbreviations: ACN, acetonitrile; A230, absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.
Additional Links: PMID-37976174
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37976174,
year = {2023},
author = {Siqueira, E and Kim, BH and Reser, L and Chow, R and Delaney, K and Esteller, M and Ross, MM and Shabanowitz, J and Hunt, DF and Guil, S and Ausiö, J},
title = {Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells.},
journal = {Epigenetics},
volume = {18},
number = {1},
pages = {2276425},
doi = {10.1080/15592294.2023.2276425},
pmid = {37976174},
issn = {1559-2308},
abstract = {An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2.Abbreviations: ACN, acetonitrile; A230, absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.},
}
RevDate: 2023-11-14
3D genome remodeling and homologous pairing during meiotic prophase of mouse oogenesis and spermatogenesis.
Developmental cell pii:S1534-5807(23)00553-1 [Epub ahead of print].
During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the chromatin remodeling in oogenesis and characteristics of homologous pairing remain largely elusive. We comprehensively compared chromatin structures and transcriptomes at successive substages of meiotic prophase in both female and male mice using low-input high-through chromosome conformation capture (Hi-C) and RNA sequencing (RNA-seq). Compartments and topologically associating domains (TADs) gradually disappeared and slowly recovered in both sexes. We found that homologs adopted different sex-conserved pairing strategies prior to and after the leptotene-to-zygotene transition, changing from long interspersed nuclear element (LINE)-enriched compartments B to short interspersed nuclear element (SINE)-enriched compartments A. We complemented marker genes and predicted the sex-specific meiotic sterile genes for each substage. This study provides valuable insights into the similarities and distinctions between sexes in chromosome architecture, homologous pairing, and transcriptome during meiotic prophase of both oogenesis and spermatogenesis.
Additional Links: PMID-37963468
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37963468,
year = {2023},
author = {He, J and Yan, A and Chen, B and Huang, J and Kee, K},
title = {3D genome remodeling and homologous pairing during meiotic prophase of mouse oogenesis and spermatogenesis.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2023.10.009},
pmid = {37963468},
issn = {1878-1551},
abstract = {During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the chromatin remodeling in oogenesis and characteristics of homologous pairing remain largely elusive. We comprehensively compared chromatin structures and transcriptomes at successive substages of meiotic prophase in both female and male mice using low-input high-through chromosome conformation capture (Hi-C) and RNA sequencing (RNA-seq). Compartments and topologically associating domains (TADs) gradually disappeared and slowly recovered in both sexes. We found that homologs adopted different sex-conserved pairing strategies prior to and after the leptotene-to-zygotene transition, changing from long interspersed nuclear element (LINE)-enriched compartments B to short interspersed nuclear element (SINE)-enriched compartments A. We complemented marker genes and predicted the sex-specific meiotic sterile genes for each substage. This study provides valuable insights into the similarities and distinctions between sexes in chromosome architecture, homologous pairing, and transcriptome during meiotic prophase of both oogenesis and spermatogenesis.},
}
RevDate: 2023-11-03
Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture.
Proceedings of the National Academy of Sciences of the United States of America, 120(45):e2313285120.
The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here, we report two 3C-derived methods, Tri-4C and Tri-HiC, which utilize multirestriction enzyme digestions for ultrafine mapping of targeted and genome-wide chromatin interaction, respectively, at up to one hundred basepair resolution. Tri-4C identified CRE loop interaction networks and quantitatively revealed their alterations underlying dynamic gene control. Tri-HiC uncovered global fine-gauge regulatory interaction networks, identifying >20-fold more enhancer:promoter (E:P) loops than in situ Hi-C. In addition to vastly improved identification of subkilobase-sized E:P loops, Tri-HiC also uncovered interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically associating domain boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high-resolution interactome maps required for characterizing fine-gauge regulatory chromatin interactions in analysis of development, homeostasis, and disease.
Additional Links: PMID-37922325
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37922325,
year = {2023},
author = {Zhu, Y and Rosenfeld, MG and Suh, Y},
title = {Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {120},
number = {45},
pages = {e2313285120},
doi = {10.1073/pnas.2313285120},
pmid = {37922325},
issn = {1091-6490},
abstract = {The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here, we report two 3C-derived methods, Tri-4C and Tri-HiC, which utilize multirestriction enzyme digestions for ultrafine mapping of targeted and genome-wide chromatin interaction, respectively, at up to one hundred basepair resolution. Tri-4C identified CRE loop interaction networks and quantitatively revealed their alterations underlying dynamic gene control. Tri-HiC uncovered global fine-gauge regulatory interaction networks, identifying >20-fold more enhancer:promoter (E:P) loops than in situ Hi-C. In addition to vastly improved identification of subkilobase-sized E:P loops, Tri-HiC also uncovered interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically associating domain boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high-resolution interactome maps required for characterizing fine-gauge regulatory chromatin interactions in analysis of development, homeostasis, and disease.},
}
RevDate: 2023-10-31
Quantifying the large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition of cell cycle.
Open biology, 13(11):230175.
Cell cycle is known to be regulated by the underlying gene network. Chromosomes, which serve as the scaffold for gene expressions, undergo significant structural reorganizations during mitosis. Understanding the mechanism of the cell cycle from the chromosome structural perspective remains a grand challenge. In this study, we applied an integrated theoretical approach to investigate large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition. We observed that the chromosome structural expansion and adaptation of the structural asphericity do not occur synchronously and attributed this behaviour to the unique unloading sequence of the two types of condensins. Furthermore, we observed that the coherent motions between the chromosomal loci are primarily enhanced within the topologically associating domains (TADs) as cells progress to the G1 phase, suggesting that TADs can be considered as both structural and dynamical units for organizing the three-dimensional chromosome. Our analysis also reveals that the quantified pathways of chromosome structural reorganization during the mitosis-to-G1 phase transition exhibit high stochasticity at the single-cell level and show nonlinear behaviours in changing TADs and contacts formed at the long-range regions. Our findings offer valuable insights into large-scale chromosome structural dynamics after mitosis.
Additional Links: PMID-37907089
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37907089,
year = {2023},
author = {Chu, X and Wang, J},
title = {Quantifying the large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition of cell cycle.},
journal = {Open biology},
volume = {13},
number = {11},
pages = {230175},
doi = {10.1098/rsob.230175},
pmid = {37907089},
issn = {2046-2441},
abstract = {Cell cycle is known to be regulated by the underlying gene network. Chromosomes, which serve as the scaffold for gene expressions, undergo significant structural reorganizations during mitosis. Understanding the mechanism of the cell cycle from the chromosome structural perspective remains a grand challenge. In this study, we applied an integrated theoretical approach to investigate large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition. We observed that the chromosome structural expansion and adaptation of the structural asphericity do not occur synchronously and attributed this behaviour to the unique unloading sequence of the two types of condensins. Furthermore, we observed that the coherent motions between the chromosomal loci are primarily enhanced within the topologically associating domains (TADs) as cells progress to the G1 phase, suggesting that TADs can be considered as both structural and dynamical units for organizing the three-dimensional chromosome. Our analysis also reveals that the quantified pathways of chromosome structural reorganization during the mitosis-to-G1 phase transition exhibit high stochasticity at the single-cell level and show nonlinear behaviours in changing TADs and contacts formed at the long-range regions. Our findings offer valuable insights into large-scale chromosome structural dynamics after mitosis.},
}
RevDate: 2023-10-29
Co-localization of clusters of TCR-regulated genes with TAD rearrangements.
BMC genomics, 24(1):650.
BACKGROUND: Gene expression has long been known to be influenced by the relative proximity of DNA regulatory elements. Topologically associating domains (TADs) are self-interacting genomic regions involved in regulating gene expression by controlling the proximity of these elements. Prior studies of TADs and their biological roles have revealed correlations between TAD changes and cellular differentiation. Here, we used Hi-C and RNA-seq data to correlate TCR-induced changes in TAD structure and gene expression in human CD4[+] T cells.
RESULTS: We developed a pipeline, Differentially Expressed Gene Enrichment Finder (DEGEF), that identifies regions of differentially expressed gene enrichment. Using DEGEF, we found that TCR-regulated genes cluster non-uniformly across the genome and that these clusters preferentially localized in regions of TAD rearrangement. Interestingly, clusters of upregulated genes preferentially formed new Hi-C contacts compared to downregulated clusters, suggesting that TCR-activated CD4[+] T cells may regulate genes by changing stimulatory contacts rather than inhibitory contacts.
CONCLUSIONS: Our observations support a significant relationship between TAD rearrangements and changes in local gene expression. These findings indicate potentially important roles for TAD rearrangements in shaping their local regulatory environments and thus driving differential expression of nearby genes during CD4[+] T cell activation. Moreover, they provide new insights into global mechanisms that regulate gene expression.
Additional Links: PMID-37898735
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37898735,
year = {2023},
author = {Gao, GF and Li, P and Leonard, WJ},
title = {Co-localization of clusters of TCR-regulated genes with TAD rearrangements.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {650},
pmid = {37898735},
issn = {1471-2164},
support = {Z99HL999999/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: Gene expression has long been known to be influenced by the relative proximity of DNA regulatory elements. Topologically associating domains (TADs) are self-interacting genomic regions involved in regulating gene expression by controlling the proximity of these elements. Prior studies of TADs and their biological roles have revealed correlations between TAD changes and cellular differentiation. Here, we used Hi-C and RNA-seq data to correlate TCR-induced changes in TAD structure and gene expression in human CD4[+] T cells.
RESULTS: We developed a pipeline, Differentially Expressed Gene Enrichment Finder (DEGEF), that identifies regions of differentially expressed gene enrichment. Using DEGEF, we found that TCR-regulated genes cluster non-uniformly across the genome and that these clusters preferentially localized in regions of TAD rearrangement. Interestingly, clusters of upregulated genes preferentially formed new Hi-C contacts compared to downregulated clusters, suggesting that TCR-activated CD4[+] T cells may regulate genes by changing stimulatory contacts rather than inhibitory contacts.
CONCLUSIONS: Our observations support a significant relationship between TAD rearrangements and changes in local gene expression. These findings indicate potentially important roles for TAD rearrangements in shaping their local regulatory environments and thus driving differential expression of nearby genes during CD4[+] T cell activation. Moreover, they provide new insights into global mechanisms that regulate gene expression.},
}
RevDate: 2023-10-27
eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.
Nucleic acids research pii:7331015 [Epub ahead of print].
Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.
Additional Links: PMID-37889077
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37889077,
year = {2023},
author = {Song, C and Zhang, G and Mu, X and Feng, C and Zhang, Q and Song, S and Zhang, Y and Yin, M and Zhang, H and Tang, H and Li, C},
title = {eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad925},
pmid = {37889077},
issn = {1362-4962},
support = {62171166//National Natural Science Foundation of China/ ; 20210002-1005 USCAT-2021-01//Affiliated Hospital of University of South China for Advanced Talents/ ; 2019M661311//China Postdoctoral Science Foundation/ ; 2023JJ30547//Natural Science Foundation of Hunan Province/ ; 20201920//Scientific Research Fund Project of Hunan Provincial Health Commission/ ; 2020SK4008//Construction of Innovative Provinces in Hunan/ ; 20214310NHYCG03//University of South China/ ; },
abstract = {Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.},
}
RevDate: 2023-10-27
Microscopic Analysis of Heterochromatin, Euchromatin and Cohesin in Cancer Cell Models and under Anti-Cancer Treatment.
Current issues in molecular biology, 45(10):8152-8172 pii:cimb45100515.
The spatial organization of euchromatin (EC) and heterochromatin (HC) appears as a cell-type specific network, which seems to have an impact on gene regulation and cell fate. The spatial organization of cohesin should thus also be characteristic for a cell type since it is involved in a TAD (topologically associating domain) formation, and thus in gene regulation or DNA repair processes. Based on the previous hypotheses and results on the general importance of heterochromatin organization on genome functions in particular, the configurations of these organizational units (EC represented by H3K4me3-positive regions, HC represented by H3K9me3-positive regions, cohesins) are investigated in the cell nuclei of different cancer and non-cancerous cell types and under different anti-cancer treatments. Confocal microscopic images of the model cell systems were used and analyzed using analytical processes of quantification created in Fiji, an imaging tool box well established in different fields of science. Human fibroblasts, breast cancer and glioblastoma cells as well as murine embryonal terato-carcinoma cells were used as these cell models and compared according to the different parameters of spatial arrangements. In addition, proliferating, quiescent and from the quiescent state reactivated fibroblasts were analyzed. In some selected cases, the cells were treated with X-rays or azacitidine. Heterogeneous results were obtained by the analyses of the configurations of the three different organizational units: granulation and a loss of H3K4me3-positive regions (EC) occurred after irradiation with 4 Gy or azacitidine treatment. While fibroblasts responded to irradiation with an increase in cohesin and granulation, in breast cancer cells, it resulted in decreases in cohesin and changes in granulation. H3K9me3-positive regions (HC) in fibroblasts experienced increased granulation, whereas in breast cancer cells, the amount of such regions increased. After azacitidine treatment, murine stem cells showed losses of cohesin and granulation and an increase in the granulation of H3K9me3-positive regions. Fibroblasts that were irradiated with 2 Gy only showed irregularities in structural amounts and granulation. Quiescent fibroblasts contained less euchromatin-related H3K4me3-positive signals and cohesin levels as well as higher heterochromatin-related H3K9me3-positive signals than non-quiescent ones. In general, fibroblasts responded more intensely to X-ray irradiation than breast cancer cells. The results indicate the usefulness of model cell systems and show that, in general, characteristic differences initially existing in chromatin and cohesin organizations result in specific responses to anti-cancer treatment.
Additional Links: PMID-37886958
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37886958,
year = {2023},
author = {Fischer, EF and Pilarczyk, G and Hausmann, M},
title = {Microscopic Analysis of Heterochromatin, Euchromatin and Cohesin in Cancer Cell Models and under Anti-Cancer Treatment.},
journal = {Current issues in molecular biology},
volume = {45},
number = {10},
pages = {8152-8172},
doi = {10.3390/cimb45100515},
pmid = {37886958},
issn = {1467-3045},
support = {02 NUK 058A//Federal Ministry of Education and Research/ ; },
abstract = {The spatial organization of euchromatin (EC) and heterochromatin (HC) appears as a cell-type specific network, which seems to have an impact on gene regulation and cell fate. The spatial organization of cohesin should thus also be characteristic for a cell type since it is involved in a TAD (topologically associating domain) formation, and thus in gene regulation or DNA repair processes. Based on the previous hypotheses and results on the general importance of heterochromatin organization on genome functions in particular, the configurations of these organizational units (EC represented by H3K4me3-positive regions, HC represented by H3K9me3-positive regions, cohesins) are investigated in the cell nuclei of different cancer and non-cancerous cell types and under different anti-cancer treatments. Confocal microscopic images of the model cell systems were used and analyzed using analytical processes of quantification created in Fiji, an imaging tool box well established in different fields of science. Human fibroblasts, breast cancer and glioblastoma cells as well as murine embryonal terato-carcinoma cells were used as these cell models and compared according to the different parameters of spatial arrangements. In addition, proliferating, quiescent and from the quiescent state reactivated fibroblasts were analyzed. In some selected cases, the cells were treated with X-rays or azacitidine. Heterogeneous results were obtained by the analyses of the configurations of the three different organizational units: granulation and a loss of H3K4me3-positive regions (EC) occurred after irradiation with 4 Gy or azacitidine treatment. While fibroblasts responded to irradiation with an increase in cohesin and granulation, in breast cancer cells, it resulted in decreases in cohesin and changes in granulation. H3K9me3-positive regions (HC) in fibroblasts experienced increased granulation, whereas in breast cancer cells, the amount of such regions increased. After azacitidine treatment, murine stem cells showed losses of cohesin and granulation and an increase in the granulation of H3K9me3-positive regions. Fibroblasts that were irradiated with 2 Gy only showed irregularities in structural amounts and granulation. Quiescent fibroblasts contained less euchromatin-related H3K4me3-positive signals and cohesin levels as well as higher heterochromatin-related H3K9me3-positive signals than non-quiescent ones. In general, fibroblasts responded more intensely to X-ray irradiation than breast cancer cells. The results indicate the usefulness of model cell systems and show that, in general, characteristic differences initially existing in chromatin and cohesin organizations result in specific responses to anti-cancer treatment.},
}
RevDate: 2023-10-26
Accessible gene borders establish a core structural unit for chromatin architecture in Arabidopsis.
Nucleic acids research, 51(19):10261-10277.
Three-dimensional (3D) chromatin structure is linked to transcriptional regulation in multicellular eukaryotes including plants. Taking advantage of high-resolution Hi-C (high-throughput chromatin conformation capture), we detected a small structural unit with 3D chromatin architecture in the Arabidopsis genome, which lacks topologically associating domains, and also in the genomes of tomato, maize, and Marchantia polymorpha. The 3D folding domain unit was usually established around an individual gene and was dependent on chromatin accessibility at the transcription start site (TSS) and transcription end site (TES). We also observed larger contact domains containing two or more neighboring genes, which were dependent on accessible border regions. Binding of transcription factors to accessible TSS/TES regions formed these gene domains. We successfully simulated these Hi-C contact maps via computational modeling using chromatin accessibility as input. Our results demonstrate that gene domains establish basic 3D chromatin architecture units that likely contribute to higher-order 3D genome folding in plants.
Additional Links: PMID-37884483
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37884483,
year = {2023},
author = {Lee, H and Seo, PJ},
title = {Accessible gene borders establish a core structural unit for chromatin architecture in Arabidopsis.},
journal = {Nucleic acids research},
volume = {51},
number = {19},
pages = {10261-10277},
doi = {10.1093/nar/gkad710},
pmid = {37884483},
issn = {1362-4962},
support = {NRF-2022R1A2B5B02001266//Basic Science Research/ ; NRF-2022R1A4A3024451//Basic Research Laboratory/ ; //National Research Foundation of Korea/ ; },
abstract = {Three-dimensional (3D) chromatin structure is linked to transcriptional regulation in multicellular eukaryotes including plants. Taking advantage of high-resolution Hi-C (high-throughput chromatin conformation capture), we detected a small structural unit with 3D chromatin architecture in the Arabidopsis genome, which lacks topologically associating domains, and also in the genomes of tomato, maize, and Marchantia polymorpha. The 3D folding domain unit was usually established around an individual gene and was dependent on chromatin accessibility at the transcription start site (TSS) and transcription end site (TES). We also observed larger contact domains containing two or more neighboring genes, which were dependent on accessible border regions. Binding of transcription factors to accessible TSS/TES regions formed these gene domains. We successfully simulated these Hi-C contact maps via computational modeling using chromatin accessibility as input. Our results demonstrate that gene domains establish basic 3D chromatin architecture units that likely contribute to higher-order 3D genome folding in plants.},
}
RevDate: 2023-10-26
A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma.
Molecular and cellular biology [Epub ahead of print].
Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. NOTCH1 is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how NOTCH1 expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the NOTCH1 locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for NOTCH1 expression and viability of FN-RMS cells. Reintroducing constitutively activated NOTCH1-ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered NOTCH1. Cells that re-establish NOTCH1 expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, SNAI2-ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses NOTCH1 expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of SNAI2/NOTCH1 effects on self-renewal and differentiation.
Additional Links: PMID-37882064
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37882064,
year = {2023},
author = {Sreenivas, P and Wang, L and Wang, M and Challa, A and Modi, P and Hensch, NR and Gryder, B and Chou, HC and Zhao, XR and Sunkel, B and Moreno-Campos, R and Khan, J and Stanton, BZ and Ignatius, MS},
title = {A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10985549.2023.2256640},
pmid = {37882064},
issn = {1098-5549},
abstract = {Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. NOTCH1 is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how NOTCH1 expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the NOTCH1 locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for NOTCH1 expression and viability of FN-RMS cells. Reintroducing constitutively activated NOTCH1-ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered NOTCH1. Cells that re-establish NOTCH1 expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, SNAI2-ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses NOTCH1 expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of SNAI2/NOTCH1 effects on self-renewal and differentiation.},
}
RevDate: 2023-10-21
3D chromatin interactions involving Drosophila insulators are infrequent but preferential and arise before TADs and transcription.
Nature communications, 14(1):6678.
In mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. In Drosophila the role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging. We describe a class of Drosophila insulators enriched at regions forming preferential chromatin interactions genome-wide. Notably, most of these 3D interactions do not involve TAD borders. Multiplexed imaging shows that these interactions occur infrequently, and only rarely involve multiple genomic regions coalescing together in space in single cells. Finally, we show that non-border preferential 3D interactions enriched in this class of insulators are present before TADs and transcription during Drosophila development. Our results are inconsistent with insulators forming stable hubs in single cells, and instead suggest that they fine-tune existing 3D chromatin interactions, providing an additional regulatory layer for transcriptional regulation.
Additional Links: PMID-37865700
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37865700,
year = {2023},
author = {Messina, O and Raynal, F and Gurgo, J and Fiche, JB and Pancaldi, V and Nollmann, M},
title = {3D chromatin interactions involving Drosophila insulators are infrequent but preferential and arise before TADs and transcription.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {6678},
pmid = {37865700},
issn = {2041-1723},
support = {episcope//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {In mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. In Drosophila the role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging. We describe a class of Drosophila insulators enriched at regions forming preferential chromatin interactions genome-wide. Notably, most of these 3D interactions do not involve TAD borders. Multiplexed imaging shows that these interactions occur infrequently, and only rarely involve multiple genomic regions coalescing together in space in single cells. Finally, we show that non-border preferential 3D interactions enriched in this class of insulators are present before TADs and transcription during Drosophila development. Our results are inconsistent with insulators forming stable hubs in single cells, and instead suggest that they fine-tune existing 3D chromatin interactions, providing an additional regulatory layer for transcriptional regulation.},
}
RevDate: 2023-10-18
Chromatin compartmentalization regulates the response to DNA damage.
Nature [Epub ahead of print].
The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated[1,2], the contribution of chromosome folding to these processes remains unclear[3]. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.
Additional Links: PMID-37853125
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37853125,
year = {2023},
author = {Arnould, C and Rocher, V and Saur, F and Bader, AS and Muzzopappa, F and Collins, S and Lesage, E and Le Bozec, B and Puget, N and Clouaire, T and Mangeat, T and Mourad, R and Ahituv, N and Noordermeer, D and Erdel, F and Bushell, M and Marnef, A and Legube, G},
title = {Chromatin compartmentalization regulates the response to DNA damage.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37853125},
issn = {1476-4687},
abstract = {The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated[1,2], the contribution of chromosome folding to these processes remains unclear[3]. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.},
}
RevDate: 2023-10-16
Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells.
Nature communications, 14(1):6519.
The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization.
Additional Links: PMID-37845234
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37845234,
year = {2023},
author = {Calandrelli, R and Wen, X and Charles Richard, JL and Luo, Z and Nguyen, TC and Chen, CJ and Qi, Z and Xue, S and Chen, W and Yan, Z and Wu, W and Zaleta-Rivera, K and Hu, R and Yu, M and Wang, Y and Li, W and Ma, J and Ren, B and Zhong, S},
title = {Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {6519},
pmid = {37845234},
issn = {2041-1723},
support = {DP1DK126138//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; U54DK107977//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01GM138852//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM136922//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HD107206//U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; DP1HD087990//U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; U01CA200147//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; UM1HG011593//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; UM1HG011585//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01HL156059//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization.},
}
RevDate: 2023-10-09
Case Report: Decrypting an interchromosomal insertion associated with Marfan's syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants.
Frontiers in genetics, 14:1244983.
Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient's neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.
Additional Links: PMID-37811140
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37811140,
year = {2023},
author = {Bonaglia, MC and Salvo, E and Sironi, M and Bertuzzo, S and Errichiello, E and Mattina, T and Zuffardi, O},
title = {Case Report: Decrypting an interchromosomal insertion associated with Marfan's syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1244983},
pmid = {37811140},
issn = {1664-8021},
abstract = {Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient's neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.},
}
RevDate: 2023-10-04
Systematic identification of inter-chromosomal interaction networks supports the existence of RNA factories.
bioRxiv : the preprint server for biology pii:2023.09.21.558852.
Most studies of genome organization have focused on intra-chromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Inter-chromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework to identify sets of loci that jointly interact in trans from Hi-C data. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans -contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands", and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes co-regulated by the same trans -acting element (i.e., a transcription or splicing factor) co-localize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same transcription factor interact with one another in trans , especially those bound by transcription factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA binding proteins correlates with trans interaction of the encoding loci. These findings support the existence of trans interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.
Additional Links: PMID-37790381
Full Text:
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37790381,
year = {2023},
author = {Hristov, BH and Noble, WS and Bertero, A},
title = {Systematic identification of inter-chromosomal interaction networks supports the existence of RNA factories.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.09.21.558852},
pmid = {37790381},
abstract = {Most studies of genome organization have focused on intra-chromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Inter-chromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework to identify sets of loci that jointly interact in trans from Hi-C data. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans -contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands", and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes co-regulated by the same trans -acting element (i.e., a transcription or splicing factor) co-localize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same transcription factor interact with one another in trans , especially those bound by transcription factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA binding proteins correlates with trans interaction of the encoding loci. These findings support the existence of trans interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.},
}
RevDate: 2023-10-03
Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.
Annals of neurology [Epub ahead of print].
OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.
METHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.
Additional Links: PMID-37787451
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37787451,
year = {2023},
author = {Parodi, L and Comeau, ME and Georgakis, MK and Mayerhofer, E and Chung, J and Falcone, GJ and Malik, R and Demel, SL and Worrall, BB and Koch, S and Testai, FD and Kittner, SJ and McCauley, JL and Hall, CE and Mayson, DJ and Elkind, MS and James, ML and Woo, D and Rosand, J and Langefeld, CD and Anderson, CD},
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.26814},
pmid = {37787451},
issn = {1531-8249},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.
METHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.},
}
RevDate: 2023-09-29
High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL.
The Journal of biological chemistry pii:S0021-9258(23)02324-4 [Epub ahead of print].
3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains (TADs) and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy (HS-AFM) imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1 and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, HS-AFM imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multi-step DNA binding mechanism mediated by dynamic protein conformational changes.
Additional Links: PMID-37774974
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37774974,
year = {2023},
author = {Kaur, P and Lu, X and Xu, Q and Irvin, EM and Pappas, C and Zhang, H and Finkelstein, IJ and Shi, Z and Tao, YJ and Yu, H and Wang, H},
title = {High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {105296},
doi = {10.1016/j.jbc.2023.105296},
pmid = {37774974},
issn = {1083-351X},
abstract = {3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains (TADs) and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy (HS-AFM) imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1 and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, HS-AFM imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multi-step DNA binding mechanism mediated by dynamic protein conformational changes.},
}
RevDate: 2023-09-28
Revisiting Assessment of Computational Methods for Hi-C Data Analysis.
International journal of molecular sciences, 24(18): pii:ijms241813814.
The performances of algorithms for Hi-C data preprocessing, the identification of topologically associating domains, and the detection of chromatin interactions and promoter-enhancer interactions have been mostly evaluated using semi-quantitative or synthetic data approaches, without utilizing the most recent methods, since 2017. In this study, we comprehensively evaluated 24 popular state-of-the-art methods for the complete end-to-end pipeline of Hi-C data analysis, using manually curated or experimentally validated benchmark datasets, including a CRISPR dataset for promoter-enhancer interaction validation. Our results indicate that, although no single method exhibited superior performance in all situations, HiC-Pro, DomainCaller, and Fit-Hi-C2 showed relatively balanced performances of most evaluation metrics for preprocessing, topologically associating domain identification, and chromatin interaction/promoter-enhancer interaction detection, respectively. The comprehensive comparison presented in this manuscript provides a reference for researchers to choose Hi-C analysis tools that best suit their needs.
Additional Links: PMID-37762117
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37762117,
year = {2023},
author = {Yang, J and Zhu, X and Wang, R and Li, M and Tang, Q},
title = {Revisiting Assessment of Computational Methods for Hi-C Data Analysis.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813814},
pmid = {37762117},
issn = {1422-0067},
support = {2021ZDZX0008//Qianzi Tang/ ; },
abstract = {The performances of algorithms for Hi-C data preprocessing, the identification of topologically associating domains, and the detection of chromatin interactions and promoter-enhancer interactions have been mostly evaluated using semi-quantitative or synthetic data approaches, without utilizing the most recent methods, since 2017. In this study, we comprehensively evaluated 24 popular state-of-the-art methods for the complete end-to-end pipeline of Hi-C data analysis, using manually curated or experimentally validated benchmark datasets, including a CRISPR dataset for promoter-enhancer interaction validation. Our results indicate that, although no single method exhibited superior performance in all situations, HiC-Pro, DomainCaller, and Fit-Hi-C2 showed relatively balanced performances of most evaluation metrics for preprocessing, topologically associating domain identification, and chromatin interaction/promoter-enhancer interaction detection, respectively. The comprehensive comparison presented in this manuscript provides a reference for researchers to choose Hi-C analysis tools that best suit their needs.},
}
RevDate: 2023-09-19
Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors.
Nature communications, 14(1):5647.
Cohesin regulates gene expression through context-specific chromatin folding mechanisms such as enhancer-promoter looping and topologically associating domain (TAD) formation by cooperating with factors such as cohesin loaders and the insulation factor CTCF. We developed a computational workflow to explore how three-dimensional (3D) structure and gene expression are regulated collectively or individually by cohesin and related factors. The main component is CustardPy, by which multi-omics datasets are compared systematically. To validate our methodology, we generated 3D genome, transcriptome, and epigenome data before and after depletion of cohesin and related factors and compared the effects of depletion. We observed diverse effects on the 3D genome and transcriptome, and gene expression changes were correlated with the splitting of TADs caused by cohesin loss. We also observed variations in long-range interactions across TADs, which correlated with their epigenomic states. These computational tools and datasets will be valuable for 3D genome and epigenome studies.
Additional Links: PMID-37726281
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37726281,
year = {2023},
author = {Nakato, R and Sakata, T and Wang, J and Nagai, LAE and Nagaoka, Y and Oba, GM and Bando, M and Shirahige, K},
title = {Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {5647},
pmid = {37726281},
issn = {2041-1723},
support = {JP23gm6310012h0004//Japan Agency for Medical Research and Development (AMED)/ ; JPMJCR18S5//MEXT | Japan Science and Technology Agency (JST)/ ; },
abstract = {Cohesin regulates gene expression through context-specific chromatin folding mechanisms such as enhancer-promoter looping and topologically associating domain (TAD) formation by cooperating with factors such as cohesin loaders and the insulation factor CTCF. We developed a computational workflow to explore how three-dimensional (3D) structure and gene expression are regulated collectively or individually by cohesin and related factors. The main component is CustardPy, by which multi-omics datasets are compared systematically. To validate our methodology, we generated 3D genome, transcriptome, and epigenome data before and after depletion of cohesin and related factors and compared the effects of depletion. We observed diverse effects on the 3D genome and transcriptome, and gene expression changes were correlated with the splitting of TADs caused by cohesin loss. We also observed variations in long-range interactions across TADs, which correlated with their epigenomic states. These computational tools and datasets will be valuable for 3D genome and epigenome studies.},
}
RevDate: 2023-09-19
Tcbf: A novel user-friendly tool for pan-3D genome analysis of topologically associating domain in eukaryotic organisms.
Bioinformatics (Oxford, England) pii:7277199 [Epub ahead of print].
SUMMARY: TAD boundaries are essential for organizing the chromatin spatial structure and regulating gene expression in eukaryotes. However, for large-scale pan-3D genome research, identifying conserved and specific TAD boundaries across different species or individuals is computationally challenging. Here, we present Tcbf, a rapid and powerful Python/R tool that integrates gene synteny blocks and homologous sequences to automatically detect conserved and specific TAD boundaries among multiple species, which can efficiently analyze huge genome datasets, greatly reduce the computational burden and enable pan-3D genome research.
Tcbf is implemented by Python/R and is available at https://github.com/TcbfGroup/Tcbf under the MIT license.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Additional Links: PMID-37725346
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37725346,
year = {2023},
author = {He, X and Huang, X and Long, Y and Liu, Z and Chang, X and Zhang, X and Wang, M},
title = {Tcbf: A novel user-friendly tool for pan-3D genome analysis of topologically associating domain in eukaryotic organisms.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btad576},
pmid = {37725346},
issn = {1367-4811},
abstract = {SUMMARY: TAD boundaries are essential for organizing the chromatin spatial structure and regulating gene expression in eukaryotes. However, for large-scale pan-3D genome research, identifying conserved and specific TAD boundaries across different species or individuals is computationally challenging. Here, we present Tcbf, a rapid and powerful Python/R tool that integrates gene synteny blocks and homologous sequences to automatically detect conserved and specific TAD boundaries among multiple species, which can efficiently analyze huge genome datasets, greatly reduce the computational burden and enable pan-3D genome research.
Tcbf is implemented by Python/R and is available at https://github.com/TcbfGroup/Tcbf under the MIT license.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
RevDate: 2023-09-13
Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.
Skeletal muscle, 13(1):15.
Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1[Cre]-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7[CreER]- or Rosa26[CreER]- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.
Additional Links: PMID-37705115
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37705115,
year = {2023},
author = {Oprescu, SN and Baumann, N and Chen, X and Sun, Q and Zhao, Y and Yue, F and Wang, H and Kuang, S},
title = {Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.},
journal = {Skeletal muscle},
volume = {13},
number = {1},
pages = {15},
pmid = {37705115},
issn = {2044-5040},
support = {F31AR077424/NH/NIH HHS/United States ; R01AR078695/NH/NIH HHS/United States ; },
abstract = {Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1[Cre]-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7[CreER]- or Rosa26[CreER]- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.},
}
RevDate: 2023-09-12
Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.
Nature communications, 14(1):5615.
Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs.
Additional Links: PMID-37699887
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37699887,
year = {2023},
author = {Chang, LH and Ghosh, S and Papale, A and Luppino, JM and Miranda, M and Piras, V and Degrouard, J and Edouard, J and Poncelet, M and Lecouvreur, N and Bloyer, S and Leforestier, A and Joyce, EF and Holcman, D and Noordermeer, D},
title = {Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {5615},
pmid = {37699887},
issn = {2041-1723},
support = {SPF201909009328//Fondation pour la Recherche Médicale (Foundation for Medical Research in France)/ ; SPF201909009284//Fondation pour la Recherche Médicale (Foundation for Medical Research in France)/ ; },
abstract = {Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs.},
}
RevDate: 2023-08-22
Hnrnpk is essential for embryonic limb bud development as a transcription activator and a collaborator of insulator protein Ctcf.
Cell death and differentiation [Epub ahead of print].
Proper development of the limb bud relies on the concordance of various signals, but its molecular mechanisms have not yet been fully illustrated. Here we report that heterogeneous nuclear ribonucleoprotein K (hnRNPK) is essential for limb bud development. Its ablation in the limb bud results in limbless forelimbs and severe deformities of the hindlimbs. In terms of mechanism, hnRNPK functions as a transcription activator for the vital genes involved in the three regulatory axes of limb bud development. Simultaneously, for the first time we elucidate that hnRNPK binds to and coordinates with the insulator protein CCCTC binding factor (CTCF) to maintain a three-dimensional chromatin architecture. Ablation of hnRNPK weakens the binding strength of CTCF to topologically associating domain (TAD) boundaries, then leading to the loose TADs, and decreased interactions between promoters and enhancers, and further decreased transcription of developmental genes. Our study establishes a fundamental and novel role of hnRNPK in regulating limb bud development.
Additional Links: PMID-37608075
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37608075,
year = {2023},
author = {Chen, Y and Zhou, T and Liao, Z and Gao, W and Wu, J and Zhang, S and Li, Y and Liu, H and Zhou, H and Xu, C and Su, P},
title = {Hnrnpk is essential for embryonic limb bud development as a transcription activator and a collaborator of insulator protein Ctcf.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {37608075},
issn = {1476-5403},
support = {92068105//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82172376//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82102518//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072385//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2021M693630//China Postdoctoral Science Foundation/ ; },
abstract = {Proper development of the limb bud relies on the concordance of various signals, but its molecular mechanisms have not yet been fully illustrated. Here we report that heterogeneous nuclear ribonucleoprotein K (hnRNPK) is essential for limb bud development. Its ablation in the limb bud results in limbless forelimbs and severe deformities of the hindlimbs. In terms of mechanism, hnRNPK functions as a transcription activator for the vital genes involved in the three regulatory axes of limb bud development. Simultaneously, for the first time we elucidate that hnRNPK binds to and coordinates with the insulator protein CCCTC binding factor (CTCF) to maintain a three-dimensional chromatin architecture. Ablation of hnRNPK weakens the binding strength of CTCF to topologically associating domain (TAD) boundaries, then leading to the loose TADs, and decreased interactions between promoters and enhancers, and further decreased transcription of developmental genes. Our study establishes a fundamental and novel role of hnRNPK in regulating limb bud development.},
}
RevDate: 2023-08-21
The dynamic role of cohesin in maintaining human genome architecture.
BioEssays : news and reviews in molecular, cellular and developmental biology [Epub ahead of print].
Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher-order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC-binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. This review aims to describe the current understanding of the dynamic nature of the cohesin-DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin-centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling.
Additional Links: PMID-37603403
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37603403,
year = {2023},
author = {Agarwal, A and Korsak, S and Choudhury, A and Plewczynski, D},
title = {The dynamic role of cohesin in maintaining human genome architecture.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e2200240},
doi = {10.1002/bies.202200240},
pmid = {37603403},
issn = {1521-1878},
abstract = {Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher-order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC-binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. This review aims to describe the current understanding of the dynamic nature of the cohesin-DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin-centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling.},
}
RevDate: 2023-08-17
Remodeling of the 3D chromatin architecture in the marine microalga Nannochloropsis oceanica during lipid accumulation.
Biotechnology for biofuels and bioproducts, 16(1):129.
BACKGROUND: Genomic three-dimensional (3D) spatial organization plays a key role in shaping gene expression and associated chromatin modification, and it is highly sensitive to environmental stress conditions. In microalgae, exposure to nitrogen stress can drive lipid accumulation, yet the associated functional alterations in the spatial organization of the microalgal genome have yet to be effectively characterized.
RESULTS: Accordingly, the present study employed RNA-seq, Hi-C, and ChIP-seq approaches to explore the relationship between 3D chromosomal architecture and gene expression during lipid accumulation in the marine microalga Nannochloropsis oceanica in response to nitrogen deprivation (ND). These analyses revealed that ND resulted in various changes in chromosomal organization, including A/B compartment transitions, topologically associating domain (TAD) shifts, and the disruption of short-range interactions. Significantly higher levels of gene expression were evident in A compartments and TAD boundary regions relative to B compartments and TAD interior regions, consistent with observed histone modification enrichment in these areas. ND-induced differentially expressed genes (DEGs) were notably enriched in altered TAD-associated regions and regions exhibiting differential genomic contact. These DEGs were subjected to Gene Ontology (GO) term analyses that indicated they were enriched in the 'fatty acid metabolism', 'response to stress', 'carbon fixation' and 'photosynthesis' functional categories, in line with the ND treatment conditions used to conduct this study. These data indicate that Nannochloropsis cells exhibit a clear association between chromatin organization and transcriptional activity under nitrogen stress conditions. Pronounced and extensive histone modifications were evident in response to ND. Observed changes in chromatin architecture were linked to shifts in histone modifications and gene expression.
CONCLUSIONS: Overall, the reprogramming of many lipid metabolism-associated genes was evident under nitrogen stress conditions with respect to both histone modifications and chromosomal organization. Together these results revealed that higher-order chromatin architecture represents a new layer that can guide efforts to understand the transcriptional regulation of lipid metabolism in nitrogen-deprived microalgae.
Additional Links: PMID-37592325
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37592325,
year = {2023},
author = {Yan, T and Wang, K and Feng, K and Gao, X and Jin, Y and Wu, H and Zhang, W and Wei, L},
title = {Remodeling of the 3D chromatin architecture in the marine microalga Nannochloropsis oceanica during lipid accumulation.},
journal = {Biotechnology for biofuels and bioproducts},
volume = {16},
number = {1},
pages = {129},
pmid = {37592325},
issn = {2731-3654},
abstract = {BACKGROUND: Genomic three-dimensional (3D) spatial organization plays a key role in shaping gene expression and associated chromatin modification, and it is highly sensitive to environmental stress conditions. In microalgae, exposure to nitrogen stress can drive lipid accumulation, yet the associated functional alterations in the spatial organization of the microalgal genome have yet to be effectively characterized.
RESULTS: Accordingly, the present study employed RNA-seq, Hi-C, and ChIP-seq approaches to explore the relationship between 3D chromosomal architecture and gene expression during lipid accumulation in the marine microalga Nannochloropsis oceanica in response to nitrogen deprivation (ND). These analyses revealed that ND resulted in various changes in chromosomal organization, including A/B compartment transitions, topologically associating domain (TAD) shifts, and the disruption of short-range interactions. Significantly higher levels of gene expression were evident in A compartments and TAD boundary regions relative to B compartments and TAD interior regions, consistent with observed histone modification enrichment in these areas. ND-induced differentially expressed genes (DEGs) were notably enriched in altered TAD-associated regions and regions exhibiting differential genomic contact. These DEGs were subjected to Gene Ontology (GO) term analyses that indicated they were enriched in the 'fatty acid metabolism', 'response to stress', 'carbon fixation' and 'photosynthesis' functional categories, in line with the ND treatment conditions used to conduct this study. These data indicate that Nannochloropsis cells exhibit a clear association between chromatin organization and transcriptional activity under nitrogen stress conditions. Pronounced and extensive histone modifications were evident in response to ND. Observed changes in chromatin architecture were linked to shifts in histone modifications and gene expression.
CONCLUSIONS: Overall, the reprogramming of many lipid metabolism-associated genes was evident under nitrogen stress conditions with respect to both histone modifications and chromosomal organization. Together these results revealed that higher-order chromatin architecture represents a new layer that can guide efforts to understand the transcriptional regulation of lipid metabolism in nitrogen-deprived microalgae.},
}
RevDate: 2023-08-14
Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains.
Frontiers in genetics, 14:1237092.
Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.
Additional Links: PMID-37576549
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37576549,
year = {2023},
author = {Tav, C and Fournier, É and Fournier, M and Khadangi, F and Baguette, A and Côté, MC and Silveira, MAD and Bérubé-Simard, FA and Bourque, G and Droit, A and Bilodeau, S},
title = {Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1237092},
pmid = {37576549},
issn = {1664-8021},
abstract = {Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.},
}
RevDate: 2023-08-10
CmpDate: 2023-08-07
Single-cell Hi-C data enhancement with deep residual and generative adversarial networks.
Bioinformatics (Oxford, England), 39(8):.
MOTIVATION: The spatial genome organization of a eukaryotic cell is important for its function. The development of single-cell technologies for probing the 3D genome conformation, especially single-cell chromosome conformation capture techniques, has enabled us to understand genome function better than before. However, due to extreme sparsity and high noise associated with single-cell Hi-C data, it is still difficult to study genome structure and function using the HiC-data of one single cell.
RESULTS: In this work, we developed a deep learning method ScHiCEDRN based on deep residual networks and generative adversarial networks for the imputation and enhancement of Hi-C data of a single cell. In terms of both image evaluation and Hi-C reproducibility metrics, ScHiCEDRN outperforms the four deep learning methods (DeepHiC, HiCPlus, HiCSR, and Loopenhance) on enhancing the raw single-cell Hi-C data of human and Drosophila. The experiments also show that it can generate single-cell Hi-C data more suitable for identifying topologically associating domain boundaries and reconstructing 3D chromosome structures than the existing methods. Moreover, ScHiCEDRN's performance generalizes well across different single cells and cell types, and it can be applied to improving population Hi-C data.
The source code of ScHiCEDRN is available at the GitHub repository: https://github.com/BioinfoMachineLearning/ScHiCEDRN.
Additional Links: PMID-37498561
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37498561,
year = {2023},
author = {Wang, Y and Guo, Z and Cheng, J},
title = {Single-cell Hi-C data enhancement with deep residual and generative adversarial networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {39},
number = {8},
pages = {},
pmid = {37498561},
issn = {1367-4811},
mesh = {Humans ; Reproducibility of Results ; *Chromosomes ; *Genome ; Chromosome Structures ; Software ; Chromatin ; },
abstract = {MOTIVATION: The spatial genome organization of a eukaryotic cell is important for its function. The development of single-cell technologies for probing the 3D genome conformation, especially single-cell chromosome conformation capture techniques, has enabled us to understand genome function better than before. However, due to extreme sparsity and high noise associated with single-cell Hi-C data, it is still difficult to study genome structure and function using the HiC-data of one single cell.
RESULTS: In this work, we developed a deep learning method ScHiCEDRN based on deep residual networks and generative adversarial networks for the imputation and enhancement of Hi-C data of a single cell. In terms of both image evaluation and Hi-C reproducibility metrics, ScHiCEDRN outperforms the four deep learning methods (DeepHiC, HiCPlus, HiCSR, and Loopenhance) on enhancing the raw single-cell Hi-C data of human and Drosophila. The experiments also show that it can generate single-cell Hi-C data more suitable for identifying topologically associating domain boundaries and reconstructing 3D chromosome structures than the existing methods. Moreover, ScHiCEDRN's performance generalizes well across different single cells and cell types, and it can be applied to improving population Hi-C data.
The source code of ScHiCEDRN is available at the GitHub repository: https://github.com/BioinfoMachineLearning/ScHiCEDRN.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Humans
Reproducibility of Results
*Chromosomes
*Genome
Chromosome Structures
Software
Chromatin
RevDate: 2023-06-13
scGHOST: Identifying single-cell 3D genome subcompartments.
bioRxiv : the preprint server for biology.
New single-cell Hi-C (scHi-C) technologies enable probing of the genome-wide cell-to-cell variability in 3D genome organization from individual cells. Several computational methods have been developed to reveal single-cell 3D genome features based on scHi-C data, including A/B compartments, topologically-associating domains, and chromatin loops. However, no scHi-C analysis method currently exists for annotating single-cell subcompartments, which are crucial for providing a more refined view of large-scale chromosome spatial localization in single cells. Here, we present SCGHOST, a single-cell subcompartment annotation method based on graph embedding with constrained random walk sampling. Applications of SCGHOST to scHi-C data and single-cell 3D genome imaging data demonstrate the reliable identification of single-cell subcompartments and offer new insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from the human prefrontal cortex, SCGHOST identifies cell type-specific subcompartments that are strongly connected to cell type-specific gene expression, suggesting the functional implications of single-cell subcompartments. Overall, SCGHOST is an effective new method for single-cell 3D genome subcompartment annotation based on scHi-C data for a broad range of biological contexts.
Additional Links: PMID-37292994
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37292994,
year = {2023},
author = {Xiong, K and Zhang, R and Ma, J},
title = {scGHOST: Identifying single-cell 3D genome subcompartments.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {37292994},
abstract = {New single-cell Hi-C (scHi-C) technologies enable probing of the genome-wide cell-to-cell variability in 3D genome organization from individual cells. Several computational methods have been developed to reveal single-cell 3D genome features based on scHi-C data, including A/B compartments, topologically-associating domains, and chromatin loops. However, no scHi-C analysis method currently exists for annotating single-cell subcompartments, which are crucial for providing a more refined view of large-scale chromosome spatial localization in single cells. Here, we present SCGHOST, a single-cell subcompartment annotation method based on graph embedding with constrained random walk sampling. Applications of SCGHOST to scHi-C data and single-cell 3D genome imaging data demonstrate the reliable identification of single-cell subcompartments and offer new insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from the human prefrontal cortex, SCGHOST identifies cell type-specific subcompartments that are strongly connected to cell type-specific gene expression, suggesting the functional implications of single-cell subcompartments. Overall, SCGHOST is an effective new method for single-cell 3D genome subcompartment annotation based on scHi-C data for a broad range of biological contexts.},
}
RevDate: 2023-07-01
CmpDate: 2023-04-25
3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.
Nature communications, 14(1):2300.
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
Additional Links: PMID-37085539
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37085539,
year = {2023},
author = {Okonechnikov, K and Camgöz, A and Chapman, O and Wani, S and Park, DE and Hübner, JM and Chakraborty, A and Pagadala, M and Bump, R and Chandran, S and Kraft, K and Acuna-Hidalgo, R and Reid, D and Sikkink, K and Mauermann, M and Juarez, EF and Jenseit, A and Robinson, JT and Pajtler, KW and Milde, T and Jäger, N and Fiesel, P and Morgan, L and Sridhar, S and Coufal, NG and Levy, M and Malicki, D and Hobbs, C and Kingsmore, S and Nahas, S and Snuderl, M and Crawford, J and Wechsler-Reya, RJ and Davidson, TB and Cotter, J and Michaiel, G and Fleischhack, G and Mundlos, S and Schmitt, A and Carter, H and Michealraj, KA and Kumar, SA and Taylor, MD and Rich, J and Buchholz, F and Mesirov, JP and Pfister, SM and Ay, F and Dixon, JR and Kool, M and Chavez, L},
title = {3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2300},
pmid = {37085539},
issn = {2041-1723},
support = {R21 NS120075/NS/NINDS NIH HHS/United States ; R01 GM074024/GM/NIGMS NIH HHS/United States ; DP5 OD023071/OD/NIH HHS/United States ; R21 NS130137/NS/NINDS NIH HHS/United States ; U24 CA210004/CA/NCI NIH HHS/United States ; U01 CA184898/CA/NCI NIH HHS/United States ; U01 CA217885/CA/NCI NIH HHS/United States ; U24 CA258406/CA/NCI NIH HHS/United States ; R21 NS116455/NS/NINDS NIH HHS/United States ; T15 LM011271/LM/NLM NIH HHS/United States ; },
mesh = {Child ; Humans ; Child, Preschool ; *Neoplasm Recurrence, Local/genetics ; Chromosomes ; Chromosome Mapping ; *Ependymoma/genetics/pathology ; Genome ; Chromatin/genetics ; },
abstract = {Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Child
Humans
Child, Preschool
*Neoplasm Recurrence, Local/genetics
Chromosomes
Chromosome Mapping
*Ependymoma/genetics/pathology
Genome
Chromatin/genetics
RevDate: 2023-04-12
CmpDate: 2023-04-12
Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging.
Nucleic acids research, 51(6):2614-2632.
Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.
Additional Links: PMID-36840746
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36840746,
year = {2023},
author = {Sabaté, T and Lelandais, B and Bertrand, E and Zimmer, C},
title = {Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging.},
journal = {Nucleic acids research},
volume = {51},
number = {6},
pages = {2614-2632},
pmid = {36840746},
issn = {1362-4962},
mesh = {*Chromosomal Proteins, Non-Histone/genetics ; *Polymers ; Chromatin ; Chromosomes ; DNA ; Cell Cycle Proteins/genetics ; },
abstract = {Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
*Chromosomal Proteins, Non-Histone/genetics
*Polymers
Chromatin
Chromosomes
DNA
Cell Cycle Proteins/genetics
RevDate: 2023-08-09
LAST-seq: single-cell RNA sequencing by direct amplification of single-stranded RNA without prior reverse transcription and second-strand synthesis.
Genome biology, 24(1):184.
Existing single-cell RNA sequencing (scRNA-seq) methods rely on reverse transcription (RT) and second-strand synthesis (SSS) to convert single-stranded RNA into double-stranded DNA prior to amplification, with the limited RT/SSS efficiency compromising RNA detectability. Here, we develop a new scRNA-seq method, Linearly Amplified Single-stranded-RNA-derived Transcriptome sequencing (LAST-seq), which directly amplifies the original single-stranded RNA molecules without prior RT/SSS. LAST-seq offers a high single-molecule capture efficiency and a low level of technical noise for single-cell transcriptome analyses. Using LAST-seq, we characterize transcriptional bursting kinetics in human cells, revealing a role of topologically associating domains in transcription regulation.
Additional Links: PMID-37559123
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37559123,
year = {2023},
author = {Lyu, J and Chen, C},
title = {LAST-seq: single-cell RNA sequencing by direct amplification of single-stranded RNA without prior reverse transcription and second-strand synthesis.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {184},
pmid = {37559123},
issn = {1474-760X},
abstract = {Existing single-cell RNA sequencing (scRNA-seq) methods rely on reverse transcription (RT) and second-strand synthesis (SSS) to convert single-stranded RNA into double-stranded DNA prior to amplification, with the limited RT/SSS efficiency compromising RNA detectability. Here, we develop a new scRNA-seq method, Linearly Amplified Single-stranded-RNA-derived Transcriptome sequencing (LAST-seq), which directly amplifies the original single-stranded RNA molecules without prior RT/SSS. LAST-seq offers a high single-molecule capture efficiency and a low level of technical noise for single-cell transcriptome analyses. Using LAST-seq, we characterize transcriptional bursting kinetics in human cells, revealing a role of topologically associating domains in transcription regulation.},
}
RevDate: 2023-08-07
3D organization of regulatory elements for transcriptional regulation in Arabidopsis.
Genome biology, 24(1):181.
BACKGROUND: Although spatial organization of compartments and topologically associating domains at large scale is relatively well studied, the spatial organization of regulatory elements at fine scale is poorly understood in plants.
RESULTS: Here we perform high-resolution chromatin interaction analysis using paired-end tag sequencing approach. We map chromatin interactions tethered with RNA polymerase II and associated with heterochromatic, transcriptionally active, and Polycomb-repressive histone modifications in Arabidopsis. Analysis of the regulatory repertoire shows that distal active cis-regulatory elements are linked to their target genes through long-range chromatin interactions with increased expression of the target genes, while poised cis-regulatory elements are linked to their target genes through long-range chromatin interactions with depressed expression of the target genes. Furthermore, we demonstrate that transcription factor MYC2 is critical for chromatin spatial organization, and propose that MYC2 occupancy and MYC2-mediated chromatin interactions coordinately facilitate transcription within the framework of 3D chromatin architecture. Analysis of functionally related gene-defined chromatin connectivity networks reveals that genes implicated in flowering-time control are functionally compartmentalized into separate subdomains via their spatial activity in the leaf or shoot apical meristem, linking active mark- or Polycomb-repressive mark-associated chromatin conformation to coordinated gene expression.
CONCLUSION: The results reveal that the regulation of gene transcription in Arabidopsis is not only by linear juxtaposition, but also by long-range chromatin interactions. Our study uncovers the fine scale genome organization of Arabidopsis and the potential roles of such organization in orchestrating transcription and development.
Additional Links: PMID-37550699
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37550699,
year = {2023},
author = {Deng, L and Zhou, Q and Zhou, J and Zhang, Q and Jia, Z and Zhu, G and Cheng, S and Cheng, L and Yin, C and Yang, C and Shen, J and Nie, J and Zhu, JK and Li, G and Zhao, L},
title = {3D organization of regulatory elements for transcriptional regulation in Arabidopsis.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {181},
pmid = {37550699},
issn = {1474-760X},
support = {32222063//National Natural Science Foundation of China/ ; 32188102//National Natural Science Foundation of China/ ; 31930032//National Natural Science Foundation of China/ ; 2662021PY005//Fundamental Research Funds for the Central Universities/ ; },
abstract = {BACKGROUND: Although spatial organization of compartments and topologically associating domains at large scale is relatively well studied, the spatial organization of regulatory elements at fine scale is poorly understood in plants.
RESULTS: Here we perform high-resolution chromatin interaction analysis using paired-end tag sequencing approach. We map chromatin interactions tethered with RNA polymerase II and associated with heterochromatic, transcriptionally active, and Polycomb-repressive histone modifications in Arabidopsis. Analysis of the regulatory repertoire shows that distal active cis-regulatory elements are linked to their target genes through long-range chromatin interactions with increased expression of the target genes, while poised cis-regulatory elements are linked to their target genes through long-range chromatin interactions with depressed expression of the target genes. Furthermore, we demonstrate that transcription factor MYC2 is critical for chromatin spatial organization, and propose that MYC2 occupancy and MYC2-mediated chromatin interactions coordinately facilitate transcription within the framework of 3D chromatin architecture. Analysis of functionally related gene-defined chromatin connectivity networks reveals that genes implicated in flowering-time control are functionally compartmentalized into separate subdomains via their spatial activity in the leaf or shoot apical meristem, linking active mark- or Polycomb-repressive mark-associated chromatin conformation to coordinated gene expression.
CONCLUSION: The results reveal that the regulation of gene transcription in Arabidopsis is not only by linear juxtaposition, but also by long-range chromatin interactions. Our study uncovers the fine scale genome organization of Arabidopsis and the potential roles of such organization in orchestrating transcription and development.},
}
RevDate: 2023-08-03
Long-range gene regulation in hormone-dependent cancer.
Nature reviews. Cancer [Epub ahead of print].
The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment.
Additional Links: PMID-37537310
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37537310,
year = {2023},
author = {Tettey, TT and Rinaldi, L and Hager, GL},
title = {Long-range gene regulation in hormone-dependent cancer.},
journal = {Nature reviews. Cancer},
volume = {},
number = {},
pages = {},
pmid = {37537310},
issn = {1474-1768},
abstract = {The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment.},
}
RevDate: 2023-08-03
Chromosome-level organization of the regulatory genome in the Drosophila nervous system.
Cell pii:S0092-8674(23)00741-9 [Epub ahead of print].
Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.
Additional Links: PMID-37536338
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37536338,
year = {2023},
author = {Mohana, G and Dorier, J and Li, X and Mouginot, M and Smith, RC and Malek, H and Leleu, M and Rodriguez, D and Khadka, J and Rosa, P and Cousin, P and Iseli, C and Restrepo, S and Guex, N and McCabe, BD and Jankowski, A and Levine, MS and Gambetta, MC},
title = {Chromosome-level organization of the regulatory genome in the Drosophila nervous system.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2023.07.008},
pmid = {37536338},
issn = {1097-4172},
abstract = {Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.},
}
RevDate: 2023-07-30
Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure.
Cell reports, 42(8):112884 pii:S2211-1247(23)00895-1 [Epub ahead of print].
NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.
Additional Links: PMID-37516964
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37516964,
year = {2023},
author = {Oka, M and Otani, M and Miyamoto, Y and Oshima, R and Adachi, J and Tomonaga, T and Asally, M and Nagaoka, Y and Tanaka, K and Toyoda, A and Ichikawa, K and Morishita, S and Isono, K and Koseki, H and Nakato, R and Ohkawa, Y and Yoneda, Y},
title = {Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure.},
journal = {Cell reports},
volume = {42},
number = {8},
pages = {112884},
doi = {10.1016/j.celrep.2023.112884},
pmid = {37516964},
issn = {2211-1247},
abstract = {NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.},
}
RevDate: 2023-07-21
HiC4D: forecasting spatiotemporal Hi-C data with residual ConvLSTM.
Briefings in bioinformatics pii:7227144 [Epub ahead of print].
The Hi-C experiments have been extensively used for the studies of genomic structures. In the last few years, spatiotemporal Hi-C has largely contributed to the investigation of genome dynamic reorganization. However, computationally modeling and forecasting spatiotemporal Hi-C data still have not been seen in the literature. We present HiC4D for dealing with the problem of forecasting spatiotemporal Hi-C data. We designed and benchmarked a novel network and named it residual ConvLSTM (ResConvLSTM), which is a combination of residual network and convolutional long short-term memory (ConvLSTM). We evaluated our new ResConvLSTM networks and compared them with the other five methods, including a naïve network (NaiveNet) that we designed as a baseline method and four outstanding video-prediction methods from the literature: ConvLSTM, spatiotemporal LSTM (ST-LSTM), self-attention LSTM (SA-LSTM) and simple video prediction (SimVP). We used eight different spatiotemporal Hi-C datasets for the blind test, including two from mouse embryogenesis, one from somatic cell nuclear transfer (SCNT) embryos, three embryogenesis datasets from different species and two non-embryogenesis datasets. Our evaluation results indicate that our ResConvLSTM networks almost always outperform the other methods on the eight blind-test datasets in terms of accurately predicting the Hi-C contact matrices at future time-steps. Our benchmarks also indicate that all of the methods that we benchmarked can successfully recover the boundaries of topologically associating domains called on the experimental Hi-C contact matrices. Taken together, our benchmarks suggest that HiC4D is an effective tool for predicting spatiotemporal Hi-C data. HiC4D is publicly available at both http://dna.cs.miami.edu/HiC4D/ and https://github.com/zwang-bioinformatics/HiC4D/.
Additional Links: PMID-37478379
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37478379,
year = {2023},
author = {Liu, T and Wang, Z},
title = {HiC4D: forecasting spatiotemporal Hi-C data with residual ConvLSTM.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad263},
pmid = {37478379},
issn = {1477-4054},
support = {/GM/NIGMS NIH HHS/United States ; R35GM137974/NH/NIH HHS/United States ; },
abstract = {The Hi-C experiments have been extensively used for the studies of genomic structures. In the last few years, spatiotemporal Hi-C has largely contributed to the investigation of genome dynamic reorganization. However, computationally modeling and forecasting spatiotemporal Hi-C data still have not been seen in the literature. We present HiC4D for dealing with the problem of forecasting spatiotemporal Hi-C data. We designed and benchmarked a novel network and named it residual ConvLSTM (ResConvLSTM), which is a combination of residual network and convolutional long short-term memory (ConvLSTM). We evaluated our new ResConvLSTM networks and compared them with the other five methods, including a naïve network (NaiveNet) that we designed as a baseline method and four outstanding video-prediction methods from the literature: ConvLSTM, spatiotemporal LSTM (ST-LSTM), self-attention LSTM (SA-LSTM) and simple video prediction (SimVP). We used eight different spatiotemporal Hi-C datasets for the blind test, including two from mouse embryogenesis, one from somatic cell nuclear transfer (SCNT) embryos, three embryogenesis datasets from different species and two non-embryogenesis datasets. Our evaluation results indicate that our ResConvLSTM networks almost always outperform the other methods on the eight blind-test datasets in terms of accurately predicting the Hi-C contact matrices at future time-steps. Our benchmarks also indicate that all of the methods that we benchmarked can successfully recover the boundaries of topologically associating domains called on the experimental Hi-C contact matrices. Taken together, our benchmarks suggest that HiC4D is an effective tool for predicting spatiotemporal Hi-C data. HiC4D is publicly available at both http://dna.cs.miami.edu/HiC4D/ and https://github.com/zwang-bioinformatics/HiC4D/.},
}
RevDate: 2023-07-19
Fundamental insights into the correlation between chromosome configuration and transcription.
Physical biology [Epub ahead of print].
Eukaryotic chromosomes exhibit a hierarchical organization that spans a spectrum of length scales, ranging from sub-regions known as loops, which typically comprise hundreds of base pairs, to much larger chromosome territories that can encompass a few mega base pairs. Chromosome conformation capture experiments that involve high-throughput sequencing methods combined with microscopy techniques have enabled a new understanding of inter- and intra-chromosomal interactions with unprecedented details. This information also provides mechanistic insights on the relationship between genome architecture and gene expression. In this article, we review the recent findings on three-dimensional interactions among chromosomes at the compartment, topologically associating domain (TAD), and loop levels and the impact of these interactions on the transcription process. We also discuss current understanding of various biophysical processes involved in multi-layer structural organization of chromosomes. Then, we discuss the relationships between gene expression and genome structure from perturbative genome-wide association studies. Furthermore, for a better understanding of how chromosome architecture and function are linked, we emphasize the role of epigenetic modifications in the regulation of gene expression. Such an understanding of the relationship between genome architecture and gene expression can provide a new perspective on the range of potential future discoveries and therapeutic research. .
Additional Links: PMID-37467757
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37467757,
year = {2023},
author = {Senapati, S and Irshad, IU and Sharma, AK and Kumar, H},
title = {Fundamental insights into the correlation between chromosome configuration and transcription.},
journal = {Physical biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1478-3975/ace8e5},
pmid = {37467757},
issn = {1478-3975},
abstract = {Eukaryotic chromosomes exhibit a hierarchical organization that spans a spectrum of length scales, ranging from sub-regions known as loops, which typically comprise hundreds of base pairs, to much larger chromosome territories that can encompass a few mega base pairs. Chromosome conformation capture experiments that involve high-throughput sequencing methods combined with microscopy techniques have enabled a new understanding of inter- and intra-chromosomal interactions with unprecedented details. This information also provides mechanistic insights on the relationship between genome architecture and gene expression. In this article, we review the recent findings on three-dimensional interactions among chromosomes at the compartment, topologically associating domain (TAD), and loop levels and the impact of these interactions on the transcription process. We also discuss current understanding of various biophysical processes involved in multi-layer structural organization of chromosomes. Then, we discuss the relationships between gene expression and genome structure from perturbative genome-wide association studies. Furthermore, for a better understanding of how chromosome architecture and function are linked, we emphasize the role of epigenetic modifications in the regulation of gene expression. Such an understanding of the relationship between genome architecture and gene expression can provide a new perspective on the range of potential future discoveries and therapeutic research. .},
}
RevDate: 2023-07-18
Epigenetic Germline Variants Predict Cancer Prognosis and Risk and Distribute Uniquely in Topologically Associating Domains.
bioRxiv : the preprint server for biology pii:2023.07.04.547722.
Cancer is a highly heterogeneous disease caused by genetic and epigenetic alterations in normal cells. A recent study uncovered methylation quantitative trait loci (meQTLs) associated with different levels of local DNA methylation in cancers. Here, we investigated whether the distribution of cancer meQTLs reflected functional organization of the genome in the form of chromatin topologically associated domains (TADs), and evaluated whether cancer meQTLs near known driver genes have the potential to influence cancer risk or progression. At TAD boundaries, we observed differences in the distribution of meQTLs when one or both of the adjacent TADs was transcriptionally active, with higher densities near inactive TADs. Furthermore, we found differences in cancer meQTL distributions in active versus inactive TADs and observed an enrichment of meQTLs in active TADs near tumor suppressors, whereas there was a depletion of such meQTLs near oncogenes. Several meQTLs were associated with cancer risk in the UKBioBank, and we were able to reproduce breast cancer risk associations in the DRIVE cohort. Survival analysis in TCGA implicated a number of meQTLs in 13 tumor types. In 10 of these, polygenic meQTL scores were associated with increased hazard in a CoxPH analysis. Risk and survival-associated meQTLs tended to affect cancer genes involved in DNA damage repair and cellular adhesion and reproduced cancer-specific associations reported in prior literature. In summary, this study provides evidence that genetic variants that influence local DNA methylation are affected by chromatin structure and can impact tumor evolution.
Additional Links: PMID-37461500
Full Text:
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37461500,
year = {2023},
author = {Goudarzi, S and Pagadala, M and Klie, A and Talwar, JV and Carter, H},
title = {Epigenetic Germline Variants Predict Cancer Prognosis and Risk and Distribute Uniquely in Topologically Associating Domains.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.07.04.547722},
pmid = {37461500},
abstract = {Cancer is a highly heterogeneous disease caused by genetic and epigenetic alterations in normal cells. A recent study uncovered methylation quantitative trait loci (meQTLs) associated with different levels of local DNA methylation in cancers. Here, we investigated whether the distribution of cancer meQTLs reflected functional organization of the genome in the form of chromatin topologically associated domains (TADs), and evaluated whether cancer meQTLs near known driver genes have the potential to influence cancer risk or progression. At TAD boundaries, we observed differences in the distribution of meQTLs when one or both of the adjacent TADs was transcriptionally active, with higher densities near inactive TADs. Furthermore, we found differences in cancer meQTL distributions in active versus inactive TADs and observed an enrichment of meQTLs in active TADs near tumor suppressors, whereas there was a depletion of such meQTLs near oncogenes. Several meQTLs were associated with cancer risk in the UKBioBank, and we were able to reproduce breast cancer risk associations in the DRIVE cohort. Survival analysis in TCGA implicated a number of meQTLs in 13 tumor types. In 10 of these, polygenic meQTL scores were associated with increased hazard in a CoxPH analysis. Risk and survival-associated meQTLs tended to affect cancer genes involved in DNA damage repair and cellular adhesion and reproduced cancer-specific associations reported in prior literature. In summary, this study provides evidence that genetic variants that influence local DNA methylation are affected by chromatin structure and can impact tumor evolution.},
}
RevDate: 2023-07-15
Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer.
Cell reports, 42(7):112778 pii:S2211-1247(23)00789-1 [Epub ahead of print].
The regulatory effect of non-coding large-scale structural variations (SVs) on proto-oncogene activation remains unclear. This study investigated SV-mediated gene dysregulation by profiling 3D cancer genome maps from 40 patients with colorectal cancer (CRC). We developed a machine learning-based method for spatial characterization of the altered 3D cancer genome. This revealed a frequent establishment of "de novo chromatin contacts" that can span multiple topologically associating domains (TADs) in addition to the canonical TAD fusion/shuffle model. Using this information, we precisely identified super-enhancer (SE)-hijacking and its clonal characteristics. Clonal SE-hijacking genes, such as TOP2B, are recurrently associated with cell-cycle/DNA-processing functions, which can potentially be used as CRC prognostic markers. Oncogene activation and increased drug resistance due to SE-hijacking were validated by reconstructing the patient's SV using CRISPR-Cas9. Collectively, the spatial and clonality-resolved analysis of the 3D cancer genome reveals regulatory principles of large-scale SVs in oncogene activation and their clinical implications.
Additional Links: PMID-37453058
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37453058,
year = {2023},
author = {Kim, K and Kim, M and Lee, AJ and Song, SH and Kang, JK and Eom, J and Kang, GH and Bae, JM and Min, S and Kim, Y and Lim, Y and Kim, HS and Kim, YJ and Kim, TY and Jung, I},
title = {Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer.},
journal = {Cell reports},
volume = {42},
number = {7},
pages = {112778},
doi = {10.1016/j.celrep.2023.112778},
pmid = {37453058},
issn = {2211-1247},
abstract = {The regulatory effect of non-coding large-scale structural variations (SVs) on proto-oncogene activation remains unclear. This study investigated SV-mediated gene dysregulation by profiling 3D cancer genome maps from 40 patients with colorectal cancer (CRC). We developed a machine learning-based method for spatial characterization of the altered 3D cancer genome. This revealed a frequent establishment of "de novo chromatin contacts" that can span multiple topologically associating domains (TADs) in addition to the canonical TAD fusion/shuffle model. Using this information, we precisely identified super-enhancer (SE)-hijacking and its clonal characteristics. Clonal SE-hijacking genes, such as TOP2B, are recurrently associated with cell-cycle/DNA-processing functions, which can potentially be used as CRC prognostic markers. Oncogene activation and increased drug resistance due to SE-hijacking were validated by reconstructing the patient's SV using CRISPR-Cas9. Collectively, the spatial and clonality-resolved analysis of the 3D cancer genome reveals regulatory principles of large-scale SVs in oncogene activation and their clinical implications.},
}
RevDate: 2023-07-14
APOE Locus-Associated Mitochondrial Function and Its Implication in Alzheimer's Disease and Aging.
International journal of molecular sciences, 24(13): pii:ijms241310440.
The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.
Additional Links: PMID-37445616
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37445616,
year = {2023},
author = {Lee, EG and Leong, L and Chen, S and Tulloch, J and Yu, CE},
title = {APOE Locus-Associated Mitochondrial Function and Its Implication in Alzheimer's Disease and Aging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {13},
pages = {},
doi = {10.3390/ijms241310440},
pmid = {37445616},
issn = {1422-0067},
support = {BX000933 and BX004823//U.S. Department of Veterans Affairs Office of Research and Development Biomedical Laboratory Research Program/ ; },
abstract = {The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.},
}
RevDate: 2023-07-12
High-throughput Oligopaint screen identifies druggable 3D genome regulators.
Nature [Epub ahead of print].
The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions[1-3]. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.
Additional Links: PMID-37438531
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37438531,
year = {2023},
author = {Park, DS and Nguyen, SC and Isenhart, R and Shah, PP and Kim, W and Barnett, RJ and Chandra, A and Luppino, JM and Harke, J and Wai, M and Walsh, PJ and Abdill, RJ and Yang, R and Lan, Y and Yoon, S and Yunker, R and Kanemaki, MT and Vahedi, G and Phillips-Cremins, JE and Jain, R and Joyce, EF},
title = {High-throughput Oligopaint screen identifies druggable 3D genome regulators.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37438531},
issn = {1476-4687},
abstract = {The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions[1-3]. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.},
}
RevDate: 2023-07-11
Predicting scale-dependent chromatin polymer properties from systematic coarse-graining.
Nature communications, 14(1):4108.
Simulating chromatin is crucial for predicting genome organization and dynamics. Although coarse-grained bead-spring polymer models are commonly used to describe chromatin, the relevant bead dimensions, elastic properties, and the nature of inter-bead potentials are unknown. Using nucleosome-resolution contact probability (Micro-C) data, we systematically coarse-grain chromatin and predict quantities essential for polymer representation of chromatin. We compute size distributions of chromatin beads for different coarse-graining scales, quantify fluctuations and distributions of bond lengths between neighboring regions, and derive effective spring constant values. Unlike the prevalent notion, our findings argue that coarse-grained chromatin beads must be considered as soft particles that can overlap, and we derive an effective inter-bead soft potential and quantify an overlap parameter. We also compute angle distributions giving insights into intrinsic folding and local bendability of chromatin. While the nucleosome-linker DNA bond angle naturally emerges from our work, we show two populations of local structural states. The bead sizes, bond lengths, and bond angles show different mean behavior at Topologically Associating Domain (TAD) boundaries and TAD interiors. We integrate our findings into a coarse-grained polymer model and provide quantitative estimates of all model parameters, which can serve as a foundational basis for all future coarse-grained chromatin simulations.
Additional Links: PMID-37433821
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37433821,
year = {2023},
author = {Kadam, S and Kumari, K and Manivannan, V and Dutta, S and Mitra, MK and Padinhateeri, R},
title = {Predicting scale-dependent chromatin polymer properties from systematic coarse-graining.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {4108},
pmid = {37433821},
issn = {2041-1723},
support = {BT/HRD/NBA/39/12/2018-19//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; },
abstract = {Simulating chromatin is crucial for predicting genome organization and dynamics. Although coarse-grained bead-spring polymer models are commonly used to describe chromatin, the relevant bead dimensions, elastic properties, and the nature of inter-bead potentials are unknown. Using nucleosome-resolution contact probability (Micro-C) data, we systematically coarse-grain chromatin and predict quantities essential for polymer representation of chromatin. We compute size distributions of chromatin beads for different coarse-graining scales, quantify fluctuations and distributions of bond lengths between neighboring regions, and derive effective spring constant values. Unlike the prevalent notion, our findings argue that coarse-grained chromatin beads must be considered as soft particles that can overlap, and we derive an effective inter-bead soft potential and quantify an overlap parameter. We also compute angle distributions giving insights into intrinsic folding and local bendability of chromatin. While the nucleosome-linker DNA bond angle naturally emerges from our work, we show two populations of local structural states. The bead sizes, bond lengths, and bond angles show different mean behavior at Topologically Associating Domain (TAD) boundaries and TAD interiors. We integrate our findings into a coarse-grained polymer model and provide quantitative estimates of all model parameters, which can serve as a foundational basis for all future coarse-grained chromatin simulations.},
}
RevDate: 2023-07-10
Three-dimensional genome structure and function.
MedComm, 4(4):e326.
Linear DNA undergoes a series of compression and folding events, forming various three-dimensional (3D) structural units in mammalian cells, including chromosomal territory, compartment, topologically associating domain, and chromatin loop. These structures play crucial roles in regulating gene expression, cell differentiation, and disease progression. Deciphering the principles underlying 3D genome folding and the molecular mechanisms governing cell fate determination remains a challenge. With advancements in high-throughput sequencing and imaging techniques, the hierarchical organization and functional roles of higher-order chromatin structures have been gradually illuminated. This review systematically discussed the structural hierarchy of the 3D genome, the effects and mechanisms of cis-regulatory elements interaction in the 3D genome for regulating spatiotemporally specific gene expression, the roles and mechanisms of dynamic changes in 3D chromatin conformation during embryonic development, and the pathological mechanisms of diseases such as congenital developmental abnormalities and cancer, which are attributed to alterations in 3D genome organization and aberrations in key structural proteins. Finally, prospects were made for the research about 3D genome structure, function, and genetic intervention, and the roles in disease development, prevention, and treatment, which may offer some clues for precise diagnosis and treatment of related diseases.
Additional Links: PMID-37426677
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37426677,
year = {2023},
author = {Liu, H and Tsai, H and Yang, M and Li, G and Bian, Q and Ding, G and Wu, D and Dai, J},
title = {Three-dimensional genome structure and function.},
journal = {MedComm},
volume = {4},
number = {4},
pages = {e326},
pmid = {37426677},
issn = {2688-2663},
abstract = {Linear DNA undergoes a series of compression and folding events, forming various three-dimensional (3D) structural units in mammalian cells, including chromosomal territory, compartment, topologically associating domain, and chromatin loop. These structures play crucial roles in regulating gene expression, cell differentiation, and disease progression. Deciphering the principles underlying 3D genome folding and the molecular mechanisms governing cell fate determination remains a challenge. With advancements in high-throughput sequencing and imaging techniques, the hierarchical organization and functional roles of higher-order chromatin structures have been gradually illuminated. This review systematically discussed the structural hierarchy of the 3D genome, the effects and mechanisms of cis-regulatory elements interaction in the 3D genome for regulating spatiotemporally specific gene expression, the roles and mechanisms of dynamic changes in 3D chromatin conformation during embryonic development, and the pathological mechanisms of diseases such as congenital developmental abnormalities and cancer, which are attributed to alterations in 3D genome organization and aberrations in key structural proteins. Finally, prospects were made for the research about 3D genome structure, function, and genetic intervention, and the roles in disease development, prevention, and treatment, which may offer some clues for precise diagnosis and treatment of related diseases.},
}
RevDate: 2023-07-07
3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction.
Science immunology, 8(85):eadg3917.
Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4[+] memory T helper 2 (TH2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.
Additional Links: PMID-37418545
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37418545,
year = {2023},
author = {Onrust-van Schoonhoven, A and de Bruijn, MJW and Stikker, B and Brouwer, RWW and Braunstahl, GJ and van IJcken, WFJ and Graf, T and Huylebroeck, D and Hendriks, RW and Stik, G and Stadhouders, R},
title = {3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction.},
journal = {Science immunology},
volume = {8},
number = {85},
pages = {eadg3917},
doi = {10.1126/sciimmunol.adg3917},
pmid = {37418545},
issn = {2470-9468},
abstract = {Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4[+] memory T helper 2 (TH2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.},
}
RevDate: 2023-07-03
Protein arginine methyltransferase 5 (Prmt5) localizes to chromatin loop anchors and modulates expression of genes at TAD boundaries during early adipogenesis.
bioRxiv : the preprint server for biology pii:2023.06.13.544859.
Protein arginine methyltransferase 5 (Prmt5) is an essential regulator of embryonic development and adult progenitor cell functions. Prmt5 expression is mis-regulated in many cancers, and the development of Prmt5 inhibitors as cancer therapeutics is an active area of research. Prmt5 functions via effects on gene expression, splicing, DNA repair, and other critical cellular processes. We examined whether Prmt5 functions broadly as a genome-wide regulator of gene transcription and higher-order chromatin interactions during the initial stages of adipogenesis using ChIP-Seq, RNA-seq, and Hi-C using 3T3-L1 cells, a frequently utilized model for adipogenesis. We observed robust genome-wide Prmt5 chromatin-binding at the onset of differentiation. Prmt5 localized to transcriptionally active genomic regions, acting as both a positive and a negative regulator. A subset of Prmt5 binding sites co-localized with mediators of chromatin organization at chromatin loop anchors. Prmt5 knockdown decreased insulation strength at the boundaries of topologically associating domains (TADs) adjacent to sites with Prmt5 and CTCF co-localization. Genes overlapping such weakened TAD boundaries showed transcriptional dysregulation. This study identifies Prmt5 as a broad regulator of gene expression, including regulation of early adipogenic factors, and reveals an unappreciated requirement for Prmt5 in maintaining strong insulation at TAD boundaries and overall chromatin organization.
Additional Links: PMID-37398486
Full Text:
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37398486,
year = {2023},
author = {Syed, SA and Shqillo, K and Nand, A and Zhan, Y and Dekker, J and Imbalzano, AN},
title = {Protein arginine methyltransferase 5 (Prmt5) localizes to chromatin loop anchors and modulates expression of genes at TAD boundaries during early adipogenesis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.06.13.544859},
pmid = {37398486},
abstract = {Protein arginine methyltransferase 5 (Prmt5) is an essential regulator of embryonic development and adult progenitor cell functions. Prmt5 expression is mis-regulated in many cancers, and the development of Prmt5 inhibitors as cancer therapeutics is an active area of research. Prmt5 functions via effects on gene expression, splicing, DNA repair, and other critical cellular processes. We examined whether Prmt5 functions broadly as a genome-wide regulator of gene transcription and higher-order chromatin interactions during the initial stages of adipogenesis using ChIP-Seq, RNA-seq, and Hi-C using 3T3-L1 cells, a frequently utilized model for adipogenesis. We observed robust genome-wide Prmt5 chromatin-binding at the onset of differentiation. Prmt5 localized to transcriptionally active genomic regions, acting as both a positive and a negative regulator. A subset of Prmt5 binding sites co-localized with mediators of chromatin organization at chromatin loop anchors. Prmt5 knockdown decreased insulation strength at the boundaries of topologically associating domains (TADs) adjacent to sites with Prmt5 and CTCF co-localization. Genes overlapping such weakened TAD boundaries showed transcriptional dysregulation. This study identifies Prmt5 as a broad regulator of gene expression, including regulation of early adipogenic factors, and reveals an unappreciated requirement for Prmt5 in maintaining strong insulation at TAD boundaries and overall chromatin organization.},
}
RevDate: 2023-06-30
Reference panel-guided super-resolution inference of Hi-C data.
Bioinformatics (Oxford, England), 39(Supplement_1):i386-i393.
MOTIVATION: Accurately assessing contacts between DNA fragments inside the nucleus with Hi-C experiment is crucial for understanding the role of 3D genome organization in gene regulation. This challenging task is due in part to the high sequencing depth of Hi-C libraries required to support high-resolution analyses. Most existing Hi-C data are collected with limited sequencing coverage, leading to poor chromatin interaction frequency estimation. Current computational approaches to enhance Hi-C signals focus on the analysis of individual Hi-C datasets of interest, without taking advantage of the facts that (i) several hundred Hi-C contact maps are publicly available and (ii) the vast majority of local spatial organizations are conserved across multiple cell types.
RESULTS: Here, we present RefHiC-SR, an attention-based deep learning framework that uses a reference panel of Hi-C datasets to facilitate the enhancement of Hi-C data resolution of a given study sample. We compare RefHiC-SR against tools that do not use reference samples and find that RefHiC-SR outperforms other programs across different cell types, and sequencing depths. It also enables high-accuracy mapping of structures such as loops and topologically associating domains.
https://github.com/BlanchetteLab/RefHiC.
Additional Links: PMID-37387127
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37387127,
year = {2023},
author = {Zhang, Y and Blanchette, M},
title = {Reference panel-guided super-resolution inference of Hi-C data.},
journal = {Bioinformatics (Oxford, England)},
volume = {39},
number = {Supplement_1},
pages = {i386-i393},
doi = {10.1093/bioinformatics/btad266},
pmid = {37387127},
issn = {1367-4811},
support = {//Genome Quebec/ ; //Canada and Genome Quebec/ ; },
abstract = {MOTIVATION: Accurately assessing contacts between DNA fragments inside the nucleus with Hi-C experiment is crucial for understanding the role of 3D genome organization in gene regulation. This challenging task is due in part to the high sequencing depth of Hi-C libraries required to support high-resolution analyses. Most existing Hi-C data are collected with limited sequencing coverage, leading to poor chromatin interaction frequency estimation. Current computational approaches to enhance Hi-C signals focus on the analysis of individual Hi-C datasets of interest, without taking advantage of the facts that (i) several hundred Hi-C contact maps are publicly available and (ii) the vast majority of local spatial organizations are conserved across multiple cell types.
RESULTS: Here, we present RefHiC-SR, an attention-based deep learning framework that uses a reference panel of Hi-C datasets to facilitate the enhancement of Hi-C data resolution of a given study sample. We compare RefHiC-SR against tools that do not use reference samples and find that RefHiC-SR outperforms other programs across different cell types, and sequencing depths. It also enables high-accuracy mapping of structures such as loops and topologically associating domains.
https://github.com/BlanchetteLab/RefHiC.},
}
RevDate: 2023-06-29
Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.
Functional & integrative genomics, 23(3):214.
In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.
Additional Links: PMID-37386239
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37386239,
year = {2023},
author = {Pandupuspitasari, NS and Khan, FA and Huang, C and Ali, A and Yousaf, MR and Shakeel, F and Putri, EM and Negara, W and Muktiani, A and Prasetiyono, BWHE and Kustiawan, L and Wahyuni, DS},
title = {Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.},
journal = {Functional & integrative genomics},
volume = {23},
number = {3},
pages = {214},
pmid = {37386239},
issn = {1438-7948},
abstract = {In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.},
}
RevDate: 2023-06-29
MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization.
EMBO reports [Epub ahead of print].
Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.
Additional Links: PMID-37381832
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37381832,
year = {2023},
author = {Zhang, Y and Cao, X and Gao, Z and Ma, X and Wang, Q and Xu, X and Cai, X and Zhang, Y and Zhang, Z and Wei, G and Wen, B},
title = {MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {e57550},
doi = {10.15252/embr.202357550},
pmid = {37381832},
issn = {1469-3178},
support = {2021YFA1100203//MOST | National Key Research and Development Program of China (NKPs)/ ; 32130019//MOST | National Natural Science Foundation of China (NSFC)/ ; },
abstract = {Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.},
}
RevDate: 2023-06-28
RAD21 is the core subunit of the cohesin complex involved in directing genome organization.
Genome biology, 24(1):155.
BACKGROUND: The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation.
RESULTS: We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes.
CONCLUSIONS: Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.
Additional Links: PMID-37381036
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37381036,
year = {2023},
author = {Sun, Y and Xu, X and Zhao, W and Zhang, Y and Chen, K and Li, Y and Wang, X and Zhang, M and Xue, B and Yu, W and Hou, Y and Wang, C and Xie, W and Li, C and Kong, D and Wang, S and Sun, Y},
title = {RAD21 is the core subunit of the cohesin complex involved in directing genome organization.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {155},
pmid = {37381036},
issn = {1474-760X},
support = {21825401//National Natural Science Foundation of China/ ; No. 2022YFA1303103//National Key Research and Development Program of China Stem Cell and Translational Research/ ; },
abstract = {BACKGROUND: The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation.
RESULTS: We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes.
CONCLUSIONS: Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.},
}
RevDate: 2023-06-16
The 3D chromatin landscape of rhabdomyosarcoma.
NAR cancer, 5(3):zcad028.
Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with a lack of precision therapy options for patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts (PDXs) to define chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative RMS (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the most common FP-RMS and FN-RMS cell lines and compared our data with PDX models. In our studies, we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains and unique patterns of structural variation. Our high-depth chromatin interactivity maps and comprehensive analyses provide context for gene regulatory events and reveal functional chromatin domains in RMS.
Additional Links: PMID-37325549
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37325549,
year = {2023},
author = {Wang, M and Sreenivas, P and Sunkel, BD and Wang, L and Ignatius, M and Stanton, BZ},
title = {The 3D chromatin landscape of rhabdomyosarcoma.},
journal = {NAR cancer},
volume = {5},
number = {3},
pages = {zcad028},
pmid = {37325549},
issn = {2632-8674},
abstract = {Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with a lack of precision therapy options for patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts (PDXs) to define chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative RMS (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the most common FP-RMS and FN-RMS cell lines and compared our data with PDX models. In our studies, we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains and unique patterns of structural variation. Our high-depth chromatin interactivity maps and comprehensive analyses provide context for gene regulatory events and reveal functional chromatin domains in RMS.},
}
RevDate: 2023-06-15
Sequential and directional insulation by conserved CTCF sites underlies the Hox timer in stembryos.
Nature genetics [Epub ahead of print].
During development, Hox genes are temporally activated according to their relative positions on their clusters, contributing to the proper identities of structures along the rostrocaudal axis. To understand the mechanism underlying this Hox timer, we used mouse embryonic stem cell-derived stembryos. Following Wnt signaling, the process involves transcriptional initiation at the anterior part of the cluster and a concomitant loading of cohesin complexes enriched on the transcribed DNA segments, that is, with an asymmetric distribution favoring the anterior part of the cluster. Chromatin extrusion then occurs with successively more posterior CTCF sites acting as transient insulators, thus generating a progressive time delay in the activation of more posterior-located genes due to long-range contacts with a flanking topologically associating domain. Mutant stembryos support this model and reveal that the presence of evolutionary conserved and regularly spaced intergenic CTCF sites controls the precision and the pace of this temporal mechanism.
Additional Links: PMID-37322110
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37322110,
year = {2023},
author = {Rekaik, H and Lopez-Delisle, L and Hintermann, A and Mascrez, B and Bochaton, C and Mayran, A and Duboule, D},
title = {Sequential and directional insulation by conserved CTCF sites underlies the Hox timer in stembryos.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {37322110},
issn = {1546-1718},
abstract = {During development, Hox genes are temporally activated according to their relative positions on their clusters, contributing to the proper identities of structures along the rostrocaudal axis. To understand the mechanism underlying this Hox timer, we used mouse embryonic stem cell-derived stembryos. Following Wnt signaling, the process involves transcriptional initiation at the anterior part of the cluster and a concomitant loading of cohesin complexes enriched on the transcribed DNA segments, that is, with an asymmetric distribution favoring the anterior part of the cluster. Chromatin extrusion then occurs with successively more posterior CTCF sites acting as transient insulators, thus generating a progressive time delay in the activation of more posterior-located genes due to long-range contacts with a flanking topologically associating domain. Mutant stembryos support this model and reveal that the presence of evolutionary conserved and regularly spaced intergenic CTCF sites controls the precision and the pace of this temporal mechanism.},
}
RevDate: 2023-06-11
TADs: Dynamic structures to create stable regulatory functions.
Current opinion in structural biology, 81:102622 pii:S0959-440X(23)00096-9 [Epub ahead of print].
Mammalian chromosomes are organized at different length scales within the cell nucleus. Topologically Associating Domains (TADs) are structural units of 3D genome organization with functions in gene regulation, DNA replication, recombination and repair. Whereas TADs were initially interpreted as insulated domains, recent studies are revealing that these domains should be interpreted as dynamic collections of actively extruding loops. This process of loop extrusion is subsequently blocked at dedicated TAD boundaries, thereby promoting intra-domain interactions over their surroundings. In this review, we discuss how mammalian TAD structure can emerge from this dynamic process and we discuss recent evidence that TAD boundaries can have regulatory functions.
Additional Links: PMID-37302180
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37302180,
year = {2023},
author = {da Costa-Nunes, JA and Noordermeer, D},
title = {TADs: Dynamic structures to create stable regulatory functions.},
journal = {Current opinion in structural biology},
volume = {81},
number = {},
pages = {102622},
doi = {10.1016/j.sbi.2023.102622},
pmid = {37302180},
issn = {1879-033X},
abstract = {Mammalian chromosomes are organized at different length scales within the cell nucleus. Topologically Associating Domains (TADs) are structural units of 3D genome organization with functions in gene regulation, DNA replication, recombination and repair. Whereas TADs were initially interpreted as insulated domains, recent studies are revealing that these domains should be interpreted as dynamic collections of actively extruding loops. This process of loop extrusion is subsequently blocked at dedicated TAD boundaries, thereby promoting intra-domain interactions over their surroundings. In this review, we discuss how mammalian TAD structure can emerge from this dynamic process and we discuss recent evidence that TAD boundaries can have regulatory functions.},
}
RevDate: 2023-06-06
CATAD: exploring topologically associating domains from an insight of core-attachment structure.
Briefings in bioinformatics pii:7188844 [Epub ahead of print].
Identifying topologically associating domains (TADs), which are considered as the basic units of chromosome structure and function, can facilitate the exploration of the 3D-structure of chromosomes. Methods have been proposed to identify TADs by detecting the boundaries of TADs or identifying the closely interacted regions as TADs, while the possible inner structure of TADs is seldom investigated. In this study, we assume that a TAD is composed of a core and its surrounding attachments, and propose a method, named CATAD, to identify TADs based on the core-attachment structure model. In CATAD, the cores of TADs are identified based on the local density and cosine similarity, and the surrounding attachments are determined based on boundary insulation. CATAD was applied to the Hi-C data of two human cell lines and two mouse cell lines, and the results show that the boundaries of TADs identified by CATAD are significantly enriched by structural proteins, histone modifications, transcription start sites and enzymes. Furthermore, CATAD outperforms other methods in many cases, in terms of the average peak, boundary tagged ratio and fold change. In addition, CATAD is robust and rarely affected by the different resolutions of Hi-C matrices. Conclusively, identifying TADs based on the core-attachment structure is useful, which may inspire researchers to explore TADs from the angles of possible spatial structures and formation process.
Additional Links: PMID-37279476
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37279476,
year = {2023},
author = {Peng, X and Li, Y and Zou, M and Kong, X and Sheng, Y},
title = {CATAD: exploring topologically associating domains from an insight of core-attachment structure.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad204},
pmid = {37279476},
issn = {1477-4054},
abstract = {Identifying topologically associating domains (TADs), which are considered as the basic units of chromosome structure and function, can facilitate the exploration of the 3D-structure of chromosomes. Methods have been proposed to identify TADs by detecting the boundaries of TADs or identifying the closely interacted regions as TADs, while the possible inner structure of TADs is seldom investigated. In this study, we assume that a TAD is composed of a core and its surrounding attachments, and propose a method, named CATAD, to identify TADs based on the core-attachment structure model. In CATAD, the cores of TADs are identified based on the local density and cosine similarity, and the surrounding attachments are determined based on boundary insulation. CATAD was applied to the Hi-C data of two human cell lines and two mouse cell lines, and the results show that the boundaries of TADs identified by CATAD are significantly enriched by structural proteins, histone modifications, transcription start sites and enzymes. Furthermore, CATAD outperforms other methods in many cases, in terms of the average peak, boundary tagged ratio and fold change. In addition, CATAD is robust and rarely affected by the different resolutions of Hi-C matrices. Conclusively, identifying TADs based on the core-attachment structure is useful, which may inspire researchers to explore TADs from the angles of possible spatial structures and formation process.},
}
RevDate: 2023-06-05
A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest.
Nature communications, 14(1):3242.
Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.
Additional Links: PMID-37277355
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37277355,
year = {2023},
author = {Kessler, S and Minoux, M and Joshi, O and Ben Zouari, Y and Ducret, S and Ross, F and Vilain, N and Salvi, A and Wolff, J and Kohler, H and Stadler, MB and Rijli, FM},
title = {A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {3242},
pmid = {37277355},
issn = {2041-1723},
abstract = {Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.},
}
RevDate: 2023-06-01
Genetic variation and domestication of horses revealed by 10 chromosome-level genomes and whole-genome resequencing.
Molecular ecology resources [Epub ahead of print].
Understanding the genetic variations of the horse (Equus caballus) genome will improve breeding conservation and welfare. However, genetic variations in long segments, such as structural variants (SVs), remain understudied. We de novo assembled 10 chromosome-level three-dimensional horse genomes, each representing a distinct breed, and analysed horse SVs using a multi-assembly approach. Our findings suggest that SVs with the accumulation of mammalian-wide interspersed repeats related to long interspersed nuclear elements might be a horse-specific mechanism to modulate genome-wide gene regulatory networks. We found that olfactory receptors were commonly loss and accumulated deleterious mutations, but no purge of deleterious mutations occurred during horse domestication. We examined the potential effects of SVs on the spatial structure of chromatin via topologically associating domains (TADs). Breed-specific TADs were significantly enriched by breed-specific SVs. We identified 4199 unique breakpoint-resolved novel insertions across all chromosomes that account for 2.84 Mb sequences missing from the reference genome. Several novel insertions might have potential functional consequences, as 519 appeared to reside within 449 gene bodies. These genes are primarily involved in pathogen recognition, innate immune responses and drug metabolism. Moreover, 37 diverse horses were resequenced. Combining this with public data, we analysed 97 horses through a comparative population genomics approach to identify the genetic basis underlying breed characteristics using Thoroughbreds as a case study. We provide new scientific evidence for horse domestication, an understanding of the genetic mechanism underlying the phenotypic evolution of horses, and a comprehensive genetic variation resource for further genetic studies of horses.
Additional Links: PMID-37259205
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37259205,
year = {2023},
author = {Gu, J and Li, S and Zhu, B and Liang, Q and Chen, B and Tang, X and Chen, C and Wu, DD and Li, Y},
title = {Genetic variation and domestication of horses revealed by 10 chromosome-level genomes and whole-genome resequencing.},
journal = {Molecular ecology resources},
volume = {},
number = {},
pages = {},
doi = {10.1111/1755-0998.13818},
pmid = {37259205},
issn = {1755-0998},
abstract = {Understanding the genetic variations of the horse (Equus caballus) genome will improve breeding conservation and welfare. However, genetic variations in long segments, such as structural variants (SVs), remain understudied. We de novo assembled 10 chromosome-level three-dimensional horse genomes, each representing a distinct breed, and analysed horse SVs using a multi-assembly approach. Our findings suggest that SVs with the accumulation of mammalian-wide interspersed repeats related to long interspersed nuclear elements might be a horse-specific mechanism to modulate genome-wide gene regulatory networks. We found that olfactory receptors were commonly loss and accumulated deleterious mutations, but no purge of deleterious mutations occurred during horse domestication. We examined the potential effects of SVs on the spatial structure of chromatin via topologically associating domains (TADs). Breed-specific TADs were significantly enriched by breed-specific SVs. We identified 4199 unique breakpoint-resolved novel insertions across all chromosomes that account for 2.84 Mb sequences missing from the reference genome. Several novel insertions might have potential functional consequences, as 519 appeared to reside within 449 gene bodies. These genes are primarily involved in pathogen recognition, innate immune responses and drug metabolism. Moreover, 37 diverse horses were resequenced. Combining this with public data, we analysed 97 horses through a comparative population genomics approach to identify the genetic basis underlying breed characteristics using Thoroughbreds as a case study. We provide new scientific evidence for horse domestication, an understanding of the genetic mechanism underlying the phenotypic evolution of horses, and a comprehensive genetic variation resource for further genetic studies of horses.},
}
RevDate: 2023-05-31
Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.
Nucleic acids research pii:7186996 [Epub ahead of print].
Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer-promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.
Additional Links: PMID-37254808
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37254808,
year = {2023},
author = {Li, D and Zhao, XY and Zhou, S and Hu, Q and Wu, F and Lee, HY},
title = {Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad468},
pmid = {37254808},
issn = {1362-4962},
abstract = {Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer-promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.},
}
RevDate: 2023-05-30
Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin.
Epigenetics & chromatin, 16(1):21.
BACKGROUND: Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.
RESULTS: We have developed a coarse-grained dynamical model of D. melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic-the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same strong effect on the predicted positioning of individual TADs -- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.
CONCLUSIONS: A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.
Additional Links: PMID-37254161
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37254161,
year = {2023},
author = {Tolokh, IS and Kinney, NA and Sharakhov, IV and Onufriev, AV},
title = {Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin.},
journal = {Epigenetics & chromatin},
volume = {16},
number = {1},
pages = {21},
pmid = {37254161},
issn = {1756-8935},
support = {R01 GM144596/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.
RESULTS: We have developed a coarse-grained dynamical model of D. melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic-the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same strong effect on the predicted positioning of individual TADs -- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.
CONCLUSIONS: A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.},
}
RevDate: 2023-05-30
Topologically associating domain underlies tissue specific expression of long intergenic non-coding RNAs.
iScience, 26(5):106640.
Accumulating evidence indicates that long intergenic non-coding RNAs (lincRNAs) show more tissue-specific expression patterns than protein-coding genes (PCGs). However, although lincRNAs are subject to canonical transcriptional regulation like PCGs, the molecular basis for the specificity of their expression patterns remains unclear. Here, using expression data and coordinates of topologically associating domains (TADs) in human tissues, we show that lincRNA loci are significantly enriched in the more internal region of TADs compared to PCGs and that lincRNAs within TADs have higher tissue specificity than those outside TADs. Based on these, we propose an analytical framework to interpret transcriptional status using lincRNA as an indicator. We applied it to hypertrophic cardiomyopathy data and found disease-specific transcriptional regulation: ectopic expression of keratin at the TAD level and derepression of myocyte differentiation-related genes by E2F1 with down-regulation of LINC00881. Our results provide understanding of the function and regulation of lincRNAs according to genomic structure.
Additional Links: PMID-37250307
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37250307,
year = {2023},
author = {Hamba, Y and Kamatani, T and Miya, F and Boroevich, KA and Tsunoda, T},
title = {Topologically associating domain underlies tissue specific expression of long intergenic non-coding RNAs.},
journal = {iScience},
volume = {26},
number = {5},
pages = {106640},
pmid = {37250307},
issn = {2589-0042},
abstract = {Accumulating evidence indicates that long intergenic non-coding RNAs (lincRNAs) show more tissue-specific expression patterns than protein-coding genes (PCGs). However, although lincRNAs are subject to canonical transcriptional regulation like PCGs, the molecular basis for the specificity of their expression patterns remains unclear. Here, using expression data and coordinates of topologically associating domains (TADs) in human tissues, we show that lincRNA loci are significantly enriched in the more internal region of TADs compared to PCGs and that lincRNAs within TADs have higher tissue specificity than those outside TADs. Based on these, we propose an analytical framework to interpret transcriptional status using lincRNA as an indicator. We applied it to hypertrophic cardiomyopathy data and found disease-specific transcriptional regulation: ectopic expression of keratin at the TAD level and derepression of myocyte differentiation-related genes by E2F1 with down-regulation of LINC00881. Our results provide understanding of the function and regulation of lincRNAs according to genomic structure.},
}
RevDate: 2023-05-16
High-resolution Hi-C maps highlight multiscale chromatin architecture reorganization during cold stress in Brachypodium distachyon.
BMC plant biology, 23(1):260.
BACKGROUND: The adaptation of plants to cold stress involves changes in gene expression profiles that are associated with epigenetic regulation. Although the three-dimensional (3D) genome architecture is considered an important epigenetic regulator, the role of 3D genome organization in the cold stress response remains unclear.
RESULTS: In this study, we developed high-resolution 3D genomic maps using control and cold-treated leaf tissue of the model plant Brachypodium distachyon using Hi-C to determine how cold stress affects the 3D genome architecture. We generated ~ 1.5 kb resolution chromatin interaction maps and showed that cold stress disrupts different levels of chromosome organization, including A/B compartment transition, a reduction in chromatin compartmentalization and the size of topologically associating domains (TADs), and loss of long-range chromatin loops. Integrating RNA-seq information, we identified cold-response genes and revealed that transcription was largely unaffected by the A/B compartment transition. The cold-response genes were predominantly localized in compartment A. In contrast, transcriptional changes are required for TAD reorganization. We demonstrated that dynamic TAD events were associated with H3K27me3 and H3K27ac state alterations. Moreover, a loss of chromatin looping, rather than a gain of looping, coincides with alterations in gene expression, indicating that chromatin loop disruption may play a more important role than loop formation in the cold-stress response.
CONCLUSIONS: Our study highlights the multiscale 3D genome reprogramming that occurs during cold stress and expands our knowledge of the mechanisms underlying transcriptional regulation in response to cold stress in plants.
Additional Links: PMID-37193952
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37193952,
year = {2023},
author = {Zhang, X and Yu, G and Dai, Y and Zhang, H and Wang, K and Han, J},
title = {High-resolution Hi-C maps highlight multiscale chromatin architecture reorganization during cold stress in Brachypodium distachyon.},
journal = {BMC plant biology},
volume = {23},
number = {1},
pages = {260},
pmid = {37193952},
issn = {1471-2229},
abstract = {BACKGROUND: The adaptation of plants to cold stress involves changes in gene expression profiles that are associated with epigenetic regulation. Although the three-dimensional (3D) genome architecture is considered an important epigenetic regulator, the role of 3D genome organization in the cold stress response remains unclear.
RESULTS: In this study, we developed high-resolution 3D genomic maps using control and cold-treated leaf tissue of the model plant Brachypodium distachyon using Hi-C to determine how cold stress affects the 3D genome architecture. We generated ~ 1.5 kb resolution chromatin interaction maps and showed that cold stress disrupts different levels of chromosome organization, including A/B compartment transition, a reduction in chromatin compartmentalization and the size of topologically associating domains (TADs), and loss of long-range chromatin loops. Integrating RNA-seq information, we identified cold-response genes and revealed that transcription was largely unaffected by the A/B compartment transition. The cold-response genes were predominantly localized in compartment A. In contrast, transcriptional changes are required for TAD reorganization. We demonstrated that dynamic TAD events were associated with H3K27me3 and H3K27ac state alterations. Moreover, a loss of chromatin looping, rather than a gain of looping, coincides with alterations in gene expression, indicating that chromatin loop disruption may play a more important role than loop formation in the cold-stress response.
CONCLUSIONS: Our study highlights the multiscale 3D genome reprogramming that occurs during cold stress and expands our knowledge of the mechanisms underlying transcriptional regulation in response to cold stress in plants.},
}
RevDate: 2023-05-10
Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.
medRxiv : the preprint server for health sciences pii:2023.04.18.23288754.
OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.
METHODS: 95,000 base pairs spanning 1q22 , including SEMA4A, SLC25A44 and PMF1 / PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A -promoter and PMF1 -enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22 , offering a potential new target for prevention of ICH and CSVD.
Additional Links: PMID-37162822
Full Text:
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37162822,
year = {2023},
author = {Parodi, L and Comeau, ME and Georgakis, MK and Mayerhofer, E and Chung, J and Falcone, GJ and Malik, R and Demel, SL and Worrall, BB and Koch, S and Testai, FD and Kittner, SJ and McCauley, JL and Hall, CE and Mayson, DJ and Elkind, MS and James, ML and Woo, D and Rosand, J and Langefeld, CD and Anderson, CD},
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.04.18.23288754},
pmid = {37162822},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.
METHODS: 95,000 base pairs spanning 1q22 , including SEMA4A, SLC25A44 and PMF1 / PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.
RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A -promoter and PMF1 -enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.
INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22 , offering a potential new target for prevention of ICH and CSVD.},
}
RevDate: 2023-05-10
DeDoc2 Identifies and Characterizes the Hierarchy and Dynamics of Chromatin TAD-Like Domains in the Single Cells.
Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Epub ahead of print].
Topologically associating domains (TADs) are functional chromatin units with hierarchical structure. However, the existence, prevalence, and dynamics of such hierarchy in single cells remain unexplored. Here, a new generation TAD-like domain (TLD) detection algorithm, named deDoc2, to decode the hierarchy of TLDs in single cells, is reported. With dynamic programming, deDoc2 seeks genome partitions with global minimal structure entropy for both whole and local contact matrix. Notably, deDoc2 outperforms state-of-the-art tools and is one of only two tools able to identify the hierarchy of TLDs in single cells. By applying deDoc2, it is showed that the hierarchy of TLDs in single cells is highly dynamic during cell cycle, as well as among human brain cortex cells, and that it is associated with cellular identity and functions. Thus, the results demonstrate the abundance of information potentially encoded by TLD hierarchy for functional regulation. The deDoc2 can be freely accessed at https://github.com/zengguangjie/deDoc2.
Additional Links: PMID-37162225
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37162225,
year = {2023},
author = {Li, A and Zeng, G and Wang, H and Li, X and Zhang, Z},
title = {DeDoc2 Identifies and Characterizes the Hierarchy and Dynamics of Chromatin TAD-Like Domains in the Single Cells.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2300366},
doi = {10.1002/advs.202300366},
pmid = {37162225},
issn = {2198-3844},
abstract = {Topologically associating domains (TADs) are functional chromatin units with hierarchical structure. However, the existence, prevalence, and dynamics of such hierarchy in single cells remain unexplored. Here, a new generation TAD-like domain (TLD) detection algorithm, named deDoc2, to decode the hierarchy of TLDs in single cells, is reported. With dynamic programming, deDoc2 seeks genome partitions with global minimal structure entropy for both whole and local contact matrix. Notably, deDoc2 outperforms state-of-the-art tools and is one of only two tools able to identify the hierarchy of TLDs in single cells. By applying deDoc2, it is showed that the hierarchy of TLDs in single cells is highly dynamic during cell cycle, as well as among human brain cortex cells, and that it is associated with cellular identity and functions. Thus, the results demonstrate the abundance of information potentially encoded by TLD hierarchy for functional regulation. The deDoc2 can be freely accessed at https://github.com/zengguangjie/deDoc2.},
}
RevDate: 2023-05-04
LPAD: using network construction and label propagation to detect topologically associating domains from Hi-C data.
Briefings in bioinformatics pii:7150739 [Epub ahead of print].
With the development of chromosome conformation capture technique, the study of spatial conformation of a genome based on Hi-C technique has made a quantum leap. Previous studies reveal that genomes are folded into hierarchy of three-dimensional (3D) structures associated with topologically associating domains (TADs), and detecting TAD boundaries is of great significance in the chromosome-level analysis of 3D genome architecture. In this paper, we propose a novel TAD identification method, LPAD, which first extracts node correlations from global interactions of chromosomes based on the random walk with restart and then builds an undirected graph from Hi-C contact matrix. Next, LPAD designs a label propagation-based approach to discover communities and generates TADs. Experimental results verify the effectiveness and quality of TAD detections compared with existing methods. Furthermore, experimental evaluation of chromatin immunoprecipitation sequencing data shows that LPAD performs high enrichment of histone modifications remarkably nearby the TAD boundaries, and these results demonstrate LPAD's advantages on TAD identification accuracy.
Additional Links: PMID-37139561
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37139561,
year = {2023},
author = {Liu, J and Li, P and Sun, J and Guo, J},
title = {LPAD: using network construction and label propagation to detect topologically associating domains from Hi-C data.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad165},
pmid = {37139561},
issn = {1477-4054},
abstract = {With the development of chromosome conformation capture technique, the study of spatial conformation of a genome based on Hi-C technique has made a quantum leap. Previous studies reveal that genomes are folded into hierarchy of three-dimensional (3D) structures associated with topologically associating domains (TADs), and detecting TAD boundaries is of great significance in the chromosome-level analysis of 3D genome architecture. In this paper, we propose a novel TAD identification method, LPAD, which first extracts node correlations from global interactions of chromosomes based on the random walk with restart and then builds an undirected graph from Hi-C contact matrix. Next, LPAD designs a label propagation-based approach to discover communities and generates TADs. Experimental results verify the effectiveness and quality of TAD detections compared with existing methods. Furthermore, experimental evaluation of chromatin immunoprecipitation sequencing data shows that LPAD performs high enrichment of histone modifications remarkably nearby the TAD boundaries, and these results demonstrate LPAD's advantages on TAD identification accuracy.},
}
RevDate: 2023-04-28
Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis.
The Journal of biological chemistry pii:S0021-9258(23)01785-4 [Epub ahead of print].
Elucidating the regulatory mechanisms of human adipose tissues (ATs) evolution is essential for understanding human-specific metabolic regulation, but the functional importance and evolutionary dynamics of three-dimensional (3D) genome organizations of ATs are not well defined. Here, we compared the 3D genome architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin conformation in ATs at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI), which have not been described previously. We found promoter-enhancer interaction (PEI) are much more evolutionarily dynamic with respect to compartmentalization and topologically associating domain (TAD). Compared to conserved PEIs, human-specific PEIs are enriched for human-specific sequence and the binding motifs of their potential mediators (transcription factors) are less conserved. Our data also demonstrated that genes involved in the evolutionarily dynamics of chromatin organization have weaker transcriptional conservation than those associated with conserved chromatin organization. Furthermore, the genes involved in energy metabolism and the maintenance of metabolic homeostasis are enriched in human-specific chromatin organization, while housekeeping genes, health-related genes and genetic variations are enriched in evolutionarily conserved compared to human-specific chromatin organization. Finally, we showed extensively divergent human-specific 3D genome organizations among one subcutaneous and three visceral ATs. Together, these findings provide a global overview of 3D genome architecture dynamics between ATs from human and mammalian models, and new insights into understanding the regulatory evolution of human ATs.
Additional Links: PMID-37116707
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37116707,
year = {2023},
author = {Liu, P and Li, D and Zhang, J and He, M and Gao, D and Wang, Y and Lin, Y and Pan, D and Li, P and Wang, T and Li, J and Kong, F and Zeng, B and Lu, L and Ma, J and Long, K and Li, G and Tang, Q and Jin, L and Li, M},
title = {Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {104757},
doi = {10.1016/j.jbc.2023.104757},
pmid = {37116707},
issn = {1083-351X},
abstract = {Elucidating the regulatory mechanisms of human adipose tissues (ATs) evolution is essential for understanding human-specific metabolic regulation, but the functional importance and evolutionary dynamics of three-dimensional (3D) genome organizations of ATs are not well defined. Here, we compared the 3D genome architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin conformation in ATs at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI), which have not been described previously. We found promoter-enhancer interaction (PEI) are much more evolutionarily dynamic with respect to compartmentalization and topologically associating domain (TAD). Compared to conserved PEIs, human-specific PEIs are enriched for human-specific sequence and the binding motifs of their potential mediators (transcription factors) are less conserved. Our data also demonstrated that genes involved in the evolutionarily dynamics of chromatin organization have weaker transcriptional conservation than those associated with conserved chromatin organization. Furthermore, the genes involved in energy metabolism and the maintenance of metabolic homeostasis are enriched in human-specific chromatin organization, while housekeeping genes, health-related genes and genetic variations are enriched in evolutionarily conserved compared to human-specific chromatin organization. Finally, we showed extensively divergent human-specific 3D genome organizations among one subcutaneous and three visceral ATs. Together, these findings provide a global overview of 3D genome architecture dynamics between ATs from human and mammalian models, and new insights into understanding the regulatory evolution of human ATs.},
}
RevDate: 2023-04-27
Three-dimensional genome rewiring in loci with human accelerated regions.
Science (New York, N.Y.), 380(6643):eabm1696.
Human accelerated regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 241 mammalian genomes. Combining deep learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.
Additional Links: PMID-37104607
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37104607,
year = {2023},
author = {Keough, KC and Whalen, S and Inoue, F and Przytycki, PF and Fair, T and Deng, C and Steyert, M and Ryu, H and Lindblad-Toh, K and Karlsson, E and , and Nowakowski, T and Ahituv, N and Pollen, A and Pollard, KS and Andrews, G and Armstrong, JC and Bianchi, M and Birren, BW and Bredemeyer, KR and Breit, AM and Christmas, MJ and Clawson, H and Damas, J and Di Palma, F and Diekhans, M and Dong, MX and Eizirik, E and Fan, K and Fanter, C and Foley, NM and Forsberg-Nilsson, K and Garcia, CJ and Gatesy, J and Gazal, S and Genereux, DP and Goodman, L and Grimshaw, J and Halsey, MK and Harris, AJ and Hickey, G and Hiller, M and Hindle, AG and Hubley, RM and Hughes, GM and Johnson, J and Juan, D and Kaplow, IM and Karlsson, EK and Keough, KC and Kirilenko, B and Koepfli, KP and Korstian, JM and Kowalczyk, A and Kozyrev, SV and Lawler, AJ and Lawless, C and Lehmann, T and Levesque, DL and Lewin, HA and Li, X and Lind, A and Lindblad-Toh, K and Mackay-Smith, A and Marinescu, VD and Marques-Bonet, T and Mason, VC and Meadows, JRS and Meyer, WK and Moore, JE and Moreira, LR and Moreno-Santillan, DD and Morrill, KM and Muntané, G and Murphy, WJ and Navarro, A and Nweeia, M and Ortmann, S and Osmanski, A and Paten, B and Paulat, NS and Pfenning, AR and Phan, BN and Pollard, KS and Pratt, HE and Ray, DA and Reilly, SK and Rosen, JR and Ruf, I and Ryan, L and Ryder, OA and Sabeti, PC and Schäffer, DE and Serres, A and Shapiro, B and Smit, AFA and Springer, M and Srinivasan, C and Steiner, C and Storer, JM and Sullivan, KAM and Sullivan, PF and Sundström, E and Supple, MA and Swofford, R and Talbot, JE and Teeling, E and Turner-Maier, J and Valenzuela, A and Wagner, F and Wallerman, O and Wang, C and Wang, J and Weng, Z and Wilder, AP and Wirthlin, ME and Xue, JR and Zhang, X},
title = {Three-dimensional genome rewiring in loci with human accelerated regions.},
journal = {Science (New York, N.Y.)},
volume = {380},
number = {6643},
pages = {eabm1696},
doi = {10.1126/science.abm1696},
pmid = {37104607},
issn = {1095-9203},
abstract = {Human accelerated regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 241 mammalian genomes. Combining deep learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.},
}
RevDate: 2023-04-26
Genome folding dynamics during the M-to-G1-phase transition.
Current opinion in genetics & development, 80:102036 pii:S0959-437X(23)00016-3 [Epub ahead of print].
All measurable features of higher-order chromosomal architecture undergo drastic reorganization as cells enter and exit mitosis. During mitosis, gene transcription is temporarily halted, the nuclear envelope is dismantled, and chromosomes undergo condensation. At this time, chromatin compartments, topologically associating domains (TADs), and loops that connect enhancers with promoters as well as CTCF/cohesin loops are dissolved. Upon G1 entry, genome organization is rebuilt in the daughter nuclei to resemble that of the mother nucleus. We survey recent studies that traced these features in relation to gene expression during the mitosis-to-G1-phase transition at high temporal resolution. Dissection of fluctuating architectural features informed the hierarchical relationships of chromosomal organization, the mechanisms by which they are formed, and their mutual (in-) dependence. These studies highlight the importance of considering the cell cycle dynamics for studies of chromosomal organization.
Additional Links: PMID-37099832
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37099832,
year = {2023},
author = {Zhang, H and Blobel, GA},
title = {Genome folding dynamics during the M-to-G1-phase transition.},
journal = {Current opinion in genetics & development},
volume = {80},
number = {},
pages = {102036},
doi = {10.1016/j.gde.2023.102036},
pmid = {37099832},
issn = {1879-0380},
abstract = {All measurable features of higher-order chromosomal architecture undergo drastic reorganization as cells enter and exit mitosis. During mitosis, gene transcription is temporarily halted, the nuclear envelope is dismantled, and chromosomes undergo condensation. At this time, chromatin compartments, topologically associating domains (TADs), and loops that connect enhancers with promoters as well as CTCF/cohesin loops are dissolved. Upon G1 entry, genome organization is rebuilt in the daughter nuclei to resemble that of the mother nucleus. We survey recent studies that traced these features in relation to gene expression during the mitosis-to-G1-phase transition at high temporal resolution. Dissection of fluctuating architectural features informed the hierarchical relationships of chromosomal organization, the mechanisms by which they are formed, and their mutual (in-) dependence. These studies highlight the importance of considering the cell cycle dynamics for studies of chromosomal organization.},
}
RevDate: 2023-04-21
DFHiC: A dilated full convolution model to enhance the resolution of Hi-C data.
Bioinformatics (Oxford, England) pii:7135829 [Epub ahead of print].
MOTIVATION: Hi-C technology has been the most widely used chromosome conformation capture(3C) experiment that measures the frequency of all paired interactions in the entire genome, which is a powerful tool for studying the 3D structure of the genome. The fineness of the constructed genome structure depends on the resolution of Hi-C data. However, due to the fact that high-resolution Hi-C data require deep sequencing and thus high experimental cost, most available Hi-C data are in low-resolution. Hence, it is essential to enhance the quality of Hi-C data by developing the effective computational methods.
RESULTS: In this work, we propose a novel method, so-called DFHiC, which generates the high-resolution Hi-C matrix from the low-resolution Hi-C matrix in the framework of the dilated convolutional neural network. The dilated convolution is able to effectively explore the global patterns in the overall Hi-C matrix by taking advantage of the information of the Hi-C matrix in a way of the longer genomic distance. Consequently, DFHiC can improve the resolution of the Hi-C matrix reliably and accurately. More importantly, the super-resolution Hi-C data enhanced by DFHiC is more in line with the real high-resolution Hi-C data than those done by the other existing methods, in terms of both chromatin significant interactions and identifying topologically associating domains (TADs).
AVAILABILITY: https://github.com/BinWangCSU/DFHiC.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Additional Links: PMID-37084258
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37084258,
year = {2023},
author = {Wang, B and Liu, K and Li, Y and Wang, J},
title = {DFHiC: A dilated full convolution model to enhance the resolution of Hi-C data.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btad211},
pmid = {37084258},
issn = {1367-4811},
abstract = {MOTIVATION: Hi-C technology has been the most widely used chromosome conformation capture(3C) experiment that measures the frequency of all paired interactions in the entire genome, which is a powerful tool for studying the 3D structure of the genome. The fineness of the constructed genome structure depends on the resolution of Hi-C data. However, due to the fact that high-resolution Hi-C data require deep sequencing and thus high experimental cost, most available Hi-C data are in low-resolution. Hence, it is essential to enhance the quality of Hi-C data by developing the effective computational methods.
RESULTS: In this work, we propose a novel method, so-called DFHiC, which generates the high-resolution Hi-C matrix from the low-resolution Hi-C matrix in the framework of the dilated convolutional neural network. The dilated convolution is able to effectively explore the global patterns in the overall Hi-C matrix by taking advantage of the information of the Hi-C matrix in a way of the longer genomic distance. Consequently, DFHiC can improve the resolution of the Hi-C matrix reliably and accurately. More importantly, the super-resolution Hi-C data enhanced by DFHiC is more in line with the real high-resolution Hi-C data than those done by the other existing methods, in terms of both chromatin significant interactions and identifying topologically associating domains (TADs).
AVAILABILITY: https://github.com/BinWangCSU/DFHiC.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
RevDate: 2023-04-20
Topologically associating domain boundaries are required for normal genome function.
Communications biology, 6(1):435.
Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes[1-3], but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.
Additional Links: PMID-37081156
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37081156,
year = {2023},
author = {Rajderkar, S and Barozzi, I and Zhu, Y and Hu, R and Zhang, Y and Li, B and Alcaina Caro, A and Fukuda-Yuzawa, Y and Kelman, G and Akeza, A and Blow, MJ and Pham, Q and Harrington, AN and Godoy, J and Meky, EM and von Maydell, K and Hunter, RD and Akiyama, JA and Novak, CS and Plajzer-Frick, I and Afzal, V and Tran, S and Lopez-Rios, J and Talkowski, ME and Lloyd, KCK and Ren, B and Dickel, DE and Visel, A and Pennacchio, LA},
title = {Topologically associating domain boundaries are required for normal genome function.},
journal = {Communications biology},
volume = {6},
number = {1},
pages = {435},
pmid = {37081156},
issn = {2399-3642},
abstract = {Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes[1-3], but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.},
}
RevDate: 2023-04-19
CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion.
Nature [Epub ahead of print].
In eukaryotes, genomic DNA is extruded into loops by cohesin[1]. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)[2,3] that have important roles in gene regulation and recombination during development and disease[1,4-7]. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear[8]. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin's loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.
Additional Links: PMID-37076620
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37076620,
year = {2023},
author = {Davidson, IF and Barth, R and Zaczek, M and van der Torre, J and Tang, W and Nagasaka, K and Janissen, R and Kerssemakers, J and Wutz, G and Dekker, C and Peters, JM},
title = {CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37076620},
issn = {1476-4687},
abstract = {In eukaryotes, genomic DNA is extruded into loops by cohesin[1]. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)[2,3] that have important roles in gene regulation and recombination during development and disease[1,4-7]. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear[8]. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin's loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.},
}
RevDate: 2023-04-18
Binding by the Polycomb complex component BMI1 and H2A monoubiquitination shape local and long-range interactions in the Arabidopsis genome.
The Plant cell pii:7127682 [Epub ahead of print].
Three-dimensional (3D) chromatin organization is highly dynamic during development and seems to play a crucial role in regulating gene expression. Self-interacting domains, commonly called topologically associating domains (TADs) or compartment domains (CDs), have been proposed as the basic structural units of chromatin organization. Surprisingly, although these units have been found in several plant species, they escaped detection in Arabidopsis (Arabidopsis thaliana). Here, we show that the Arabidopsis genome is partitioned into contiguous CDs with different epigenetic features, which are required to maintain appropriate intra-CD and long-range interactions. Consistent with this notion, the histone-modifying Polycomb group machinery is involved in 3D chromatin organization. Yet, while it is clear that Polycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) helps establish local and long-range chromatin interactions in plants, the implications of PRC1-mediated histone H2A monoubiquitination on lysine 121 (H2AK121ub) are unclear. We found that PRC1, together with PRC2, maintains intra-CD interactions, but it also hinders the formation of H3K4me3-enriched local chromatin loops when acting independently of PRC2. Moreover, the loss of PRC1 or PRC2 activity differentially affects long-range chromatin interactions, and these 3D changes differentially affect gene expression. Our results suggest that H2AK121ub helps prevent the formation of transposable element/H3K27me1-rich long loops and serves as a docking point for H3K27me3 incorporation.
Additional Links: PMID-37070946
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37070946,
year = {2023},
author = {Yin, X and Romero-Campero, FJ and Yang, M and Baile, F and Cao, Y and Shu, J and Luo, L and Wang, D and Sun, S and Yan, P and Gong, Z and Mo, X and Qin, G and Calonje, M and Zhou, Y},
title = {Binding by the Polycomb complex component BMI1 and H2A monoubiquitination shape local and long-range interactions in the Arabidopsis genome.},
journal = {The Plant cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/plcell/koad112},
pmid = {37070946},
issn = {1532-298X},
abstract = {Three-dimensional (3D) chromatin organization is highly dynamic during development and seems to play a crucial role in regulating gene expression. Self-interacting domains, commonly called topologically associating domains (TADs) or compartment domains (CDs), have been proposed as the basic structural units of chromatin organization. Surprisingly, although these units have been found in several plant species, they escaped detection in Arabidopsis (Arabidopsis thaliana). Here, we show that the Arabidopsis genome is partitioned into contiguous CDs with different epigenetic features, which are required to maintain appropriate intra-CD and long-range interactions. Consistent with this notion, the histone-modifying Polycomb group machinery is involved in 3D chromatin organization. Yet, while it is clear that Polycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) helps establish local and long-range chromatin interactions in plants, the implications of PRC1-mediated histone H2A monoubiquitination on lysine 121 (H2AK121ub) are unclear. We found that PRC1, together with PRC2, maintains intra-CD interactions, but it also hinders the formation of H3K4me3-enriched local chromatin loops when acting independently of PRC2. Moreover, the loss of PRC1 or PRC2 activity differentially affects long-range chromatin interactions, and these 3D changes differentially affect gene expression. Our results suggest that H2AK121ub helps prevent the formation of transposable element/H3K27me1-rich long loops and serves as a docking point for H3K27me3 incorporation.},
}
RevDate: 2023-04-17
Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection.
Frontiers in immunology, 14:1161522.
BACKGROUNDS: Hepatitis B virus (HBV) infection is a major risk factor for chronic liver diseases and liver cancer (mainly hepatocellular carcinoma, HCC), while the underlying mechanisms and host-virus interactions are still largely elusive.
METHODS: We applied HiC sequencing to HepG2 (HBV-) and HepG2-2.2.15 (HBV+) cell lines and combined them with public HCC single-cell RNA-seq data, HCC bulk RNA-seq data, and both genomic and epigenomic ChIP-seq data to reveal potential disease mechanisms of HBV infection and host-virus interactions reflected by 3D genome organization.
RESULTS: We found that HBV enhanced overall proximal chromatin interactions (CIs) of liver cells and primarily affected regional CIs on chromosomes 13, 14, 17, and 22. Interestingly, HBV altered the boundaries of many topologically associating domains (TADs), and genes nearby these boundaries showed functional enrichment in cell adhesion which may promote cancer metastasis. Moreover, A/B compartment analysis revealed dramatic changes on chromosomes 9, 13 and 21, with more B compartments (inactive or closed) shifting to A compartments (active or open). The A-to-B regions (closing) harbored enhancers enriched in the regulation of inflammatory responses, whereas B-to-A regions (opening) were enriched for transposable elements (TE). Furthermore, we identified large HBV-induced structural variations (SVs) that disrupted tumor suppressors, NLGN4Y and PROS1. Finally, we examined differentially expressed genes and TEs in single hepatocytes with or without HBV infection, by using single-cell RNA-seq data. Consistent with our HiC sequencing findings, two upregulated genes that promote HBV replication, HNF4A and NR5A2, were located in regions with HBV-enhanced CIs, and five TEs were located in HBV-activated regions. Therefore, HBV may promote liver diseases by affecting the human 3D genome structure.
CONCLUSION: Our work promotes mechanistic understanding of HBV infection and host-virus interactions related to liver diseases that affect billions of people worldwide. Our findings may also have implications for novel immunotherapeutic strategies targeting HBV infection.
Additional Links: PMID-37063858
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37063858,
year = {2023},
author = {Guo, M and Yao, Z and Jiang, C and Songyang, Z and Gan, L and Xiong, Y},
title = {Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1161522},
pmid = {37063858},
issn = {1664-3224},
abstract = {BACKGROUNDS: Hepatitis B virus (HBV) infection is a major risk factor for chronic liver diseases and liver cancer (mainly hepatocellular carcinoma, HCC), while the underlying mechanisms and host-virus interactions are still largely elusive.
METHODS: We applied HiC sequencing to HepG2 (HBV-) and HepG2-2.2.15 (HBV+) cell lines and combined them with public HCC single-cell RNA-seq data, HCC bulk RNA-seq data, and both genomic and epigenomic ChIP-seq data to reveal potential disease mechanisms of HBV infection and host-virus interactions reflected by 3D genome organization.
RESULTS: We found that HBV enhanced overall proximal chromatin interactions (CIs) of liver cells and primarily affected regional CIs on chromosomes 13, 14, 17, and 22. Interestingly, HBV altered the boundaries of many topologically associating domains (TADs), and genes nearby these boundaries showed functional enrichment in cell adhesion which may promote cancer metastasis. Moreover, A/B compartment analysis revealed dramatic changes on chromosomes 9, 13 and 21, with more B compartments (inactive or closed) shifting to A compartments (active or open). The A-to-B regions (closing) harbored enhancers enriched in the regulation of inflammatory responses, whereas B-to-A regions (opening) were enriched for transposable elements (TE). Furthermore, we identified large HBV-induced structural variations (SVs) that disrupted tumor suppressors, NLGN4Y and PROS1. Finally, we examined differentially expressed genes and TEs in single hepatocytes with or without HBV infection, by using single-cell RNA-seq data. Consistent with our HiC sequencing findings, two upregulated genes that promote HBV replication, HNF4A and NR5A2, were located in regions with HBV-enhanced CIs, and five TEs were located in HBV-activated regions. Therefore, HBV may promote liver diseases by affecting the human 3D genome structure.
CONCLUSION: Our work promotes mechanistic understanding of HBV infection and host-virus interactions related to liver diseases that affect billions of people worldwide. Our findings may also have implications for novel immunotherapeutic strategies targeting HBV infection.},
}
RevDate: 2023-04-13
Dynamic chromatin architectures provide insights into the genetics of cattle myogenesis.
Journal of animal science and biotechnology, 14(1):59.
BACKGROUND: Sharply increased beef consumption is propelling the genetic improvement projects of beef cattle in China. Three-dimensional genome structure is confirmed to be an important layer of transcription regulation. Although genome-wide interaction data of several livestock species have already been produced, the genome structure states and its regulatory rules in cattle muscle are still limited.
RESULTS: Here we present the first 3D genome data in Longissimus dorsi muscle of fetal and adult cattle (Bos taurus). We showed that compartments, topologically associating domains (TADs), and loop undergo re-organization and the structure dynamics were consistent with transcriptomic divergence during muscle development. Furthermore, we annotated cis-regulatory elements in cattle genome during myogenesis and demonstrated the enrichments of promoter and enhancer in selection sweeps. We further validated the regulatory function of one HMGA2 intronic enhancer near a strong sweep region on primary bovine myoblast proliferation.
CONCLUSIONS: Our data provide key insights of the regulatory function of high order chromatin structure and cattle myogenic biology, which will benefit the progress of genetic improvement of beef cattle.
Additional Links: PMID-37055796
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37055796,
year = {2023},
author = {Cheng, J and Cao, X and Wang, X and Wang, J and Yue, B and Sun, W and Huang, Y and Lan, X and Ren, G and Lei, C and Chen, H},
title = {Dynamic chromatin architectures provide insights into the genetics of cattle myogenesis.},
journal = {Journal of animal science and biotechnology},
volume = {14},
number = {1},
pages = {59},
pmid = {37055796},
issn = {1674-9782},
abstract = {BACKGROUND: Sharply increased beef consumption is propelling the genetic improvement projects of beef cattle in China. Three-dimensional genome structure is confirmed to be an important layer of transcription regulation. Although genome-wide interaction data of several livestock species have already been produced, the genome structure states and its regulatory rules in cattle muscle are still limited.
RESULTS: Here we present the first 3D genome data in Longissimus dorsi muscle of fetal and adult cattle (Bos taurus). We showed that compartments, topologically associating domains (TADs), and loop undergo re-organization and the structure dynamics were consistent with transcriptomic divergence during muscle development. Furthermore, we annotated cis-regulatory elements in cattle genome during myogenesis and demonstrated the enrichments of promoter and enhancer in selection sweeps. We further validated the regulatory function of one HMGA2 intronic enhancer near a strong sweep region on primary bovine myoblast proliferation.
CONCLUSIONS: Our data provide key insights of the regulatory function of high order chromatin structure and cattle myogenic biology, which will benefit the progress of genetic improvement of beef cattle.},
}
RevDate: 2023-04-13
Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations.
International journal of molecular sciences, 24(7): pii:ijms24076395.
In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC-binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF-DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF's importance in the regulation of chromatin architecture and gene expression.
Additional Links: PMID-37047368
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37047368,
year = {2023},
author = {Mao, A and Chen, C and Portillo-Ledesma, S and Schlick, T},
title = {Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations.},
journal = {International journal of molecular sciences},
volume = {24},
number = {7},
pages = {},
doi = {10.3390/ijms24076395},
pmid = {37047368},
issn = {1422-0067},
support = {R35-GM122562/NH/NIH HHS/United States ; },
abstract = {In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC-binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF-DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF's importance in the regulation of chromatin architecture and gene expression.},
}
RevDate: 2023-04-11
Disrupted chromatin architecture in olfactory sensory neurons: looking for the link from COVID-19 infection to anosmia.
Scientific reports, 13(1):5906.
We tackle here genomic mechanisms of a rapid onset and recovery from anosmia-a potential diagnostic indicator for early-stage COVID-19 infection. Based on previous observations on how olfactory receptor (OR) gene expression is regulated via chromatin structure in mice, we hypothesized that the disruption of the OR gene expression and, respectively, deficiency of the OR function can be caused by chromatin reorganization taking place upon SARS-CoV-2 infection. We obtained chromatin ensemble reconstructions from COVID-19 patients and control samples using our original computational framework for the whole-genome 3D chromatin ensemble reconstruction. Specifically, we used megabase-scale structural units and effective interactions between them obtained in the Markov State modelling of the Hi-C contact network as an unput in the stochastic embedding procedure of the whole-genome 3D chromatin ensemble reconstruction. We have also developed here a new procedure for analyzing fine structural hierarchy with (sub)TAD-size units in local chromatin regions, which we apply here to parts of chromosomes containing OR genes and corresponding regulatory elements. We observed structural modifications in COVID-19 patients on different levels of chromatin organization, from the alteration of whole genome structure and chromosomal intermingling to reorganization of contacts between chromatin loops at the level of topologically associating domains. While complementary data on known regulatory elements point to potential pathology-associated changes within the overall picture of chromatin alterations, further investigation using additional epigenetic factors mapped on 3D reconstructions with improved resolution will be required for better understanding of anosmia caused by SARS-CoV-2 infection.
Additional Links: PMID-37041182
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37041182,
year = {2023},
author = {Tan, ZW and Toong, PJ and Guarnera, E and Berezovsky, IN},
title = {Disrupted chromatin architecture in olfactory sensory neurons: looking for the link from COVID-19 infection to anosmia.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {5906},
pmid = {37041182},
issn = {2045-2322},
abstract = {We tackle here genomic mechanisms of a rapid onset and recovery from anosmia-a potential diagnostic indicator for early-stage COVID-19 infection. Based on previous observations on how olfactory receptor (OR) gene expression is regulated via chromatin structure in mice, we hypothesized that the disruption of the OR gene expression and, respectively, deficiency of the OR function can be caused by chromatin reorganization taking place upon SARS-CoV-2 infection. We obtained chromatin ensemble reconstructions from COVID-19 patients and control samples using our original computational framework for the whole-genome 3D chromatin ensemble reconstruction. Specifically, we used megabase-scale structural units and effective interactions between them obtained in the Markov State modelling of the Hi-C contact network as an unput in the stochastic embedding procedure of the whole-genome 3D chromatin ensemble reconstruction. We have also developed here a new procedure for analyzing fine structural hierarchy with (sub)TAD-size units in local chromatin regions, which we apply here to parts of chromosomes containing OR genes and corresponding regulatory elements. We observed structural modifications in COVID-19 patients on different levels of chromatin organization, from the alteration of whole genome structure and chromosomal intermingling to reorganization of contacts between chromatin loops at the level of topologically associating domains. While complementary data on known regulatory elements point to potential pathology-associated changes within the overall picture of chromatin alterations, further investigation using additional epigenetic factors mapped on 3D reconstructions with improved resolution will be required for better understanding of anosmia caused by SARS-CoV-2 infection.},
}
RevDate: 2023-04-11
Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation.
Nature communications, 14(1):2034.
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.
Additional Links: PMID-37041138
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37041138,
year = {2023},
author = {Melo, US and Jatzlau, J and Prada-Medina, CA and Flex, E and Hartmann, S and Ali, S and Schöpflin, R and Bernardini, L and Ciolfi, A and Moeinzadeh, MH and Klever, MK and Altay, A and Vallecillo-García, P and Carpentieri, G and Delledonne, M and Ort, MJ and Schwestka, M and Ferrero, GB and Tartaglia, M and Brusco, A and Gossen, M and Strunk, D and Geißler, S and Mundlos, S and Stricker, S and Knaus, P and Giorgio, E and Spielmann, M},
title = {Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2034},
pmid = {37041138},
issn = {2041-1723},
abstract = {Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.},
}
RevDate: 2023-04-05
Spatiotemporal Epigenetic Control of the Histone Gene Chromatin Landscape during the Cell Cycle.
Critical reviews in eukaryotic gene expression, 33(3):85-97.
Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.
Additional Links: PMID-37017672
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37017672,
year = {2023},
author = {Fritz, AJ and Ghule, PN and Toor, R and Dillac, L and Perelman, J and Boyd, J and Lian, JB and Gordon, JAR and Frietze, S and Van Wijnen, A and Stein, JL and Stein, GS},
title = {Spatiotemporal Epigenetic Control of the Histone Gene Chromatin Landscape during the Cell Cycle.},
journal = {Critical reviews in eukaryotic gene expression},
volume = {33},
number = {3},
pages = {85-97},
doi = {10.1615/CritRevEukaryotGeneExpr.2022046190},
pmid = {37017672},
issn = {1045-4403},
abstract = {Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.},
}
RevDate: 2023-04-04
NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization.
Genome biology, 24(1):64.
BACKGROUND: The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance.
RESULTS: To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction.
CONCLUSIONS: In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.
Additional Links: PMID-37016431
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37016431,
year = {2023},
author = {Narang, S and Evensen, NA and Saliba, J and Pierro, J and Loh, ML and Brown, PA and Kolekar, P and Mulder, H and Shao, Y and Easton, J and Ma, X and Tsirigos, A and Carroll, WL},
title = {NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {64},
pmid = {37016431},
issn = {1474-760X},
abstract = {BACKGROUND: The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance.
RESULTS: To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction.
CONCLUSIONS: In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.},
}
RevDate: 2023-04-03
Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft.
Scientific reports, 13(1):5420.
Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.
Additional Links: PMID-37012431
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37012431,
year = {2023},
author = {Dozmorov, MG and Marshall, MA and Rashid, NS and Grible, JM and Valentine, A and Olex, AL and Murthy, K and Chakraborty, A and Reyna, J and Figueroa, DS and Hinojosa-Gonzalez, L and Da-Inn Lee, E and Baur, BA and Roy, S and Ay, F and Harrell, JC},
title = {Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {5420},
pmid = {37012431},
issn = {2045-2322},
support = {R35-GM128938/GM/NIGMS NIH HHS/United States ; R35-GM128938/GM/NIGMS NIH HHS/United States ; 1R01CA246182-01A1/CA/NCI NIH HHS/United States ; CCR19608826/KOMEN/Susan G. Komen/United States ; },
abstract = {Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.},
}
RevDate: 2023-03-31
SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites.
Cell reports, 42(4):112323 pii:S2211-1247(23)00334-0 [Epub ahead of print].
Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in spatial genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells leads to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple levels, including compartments, topologically associating domains, and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 leads to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical regulators of T cell activation. The loss of SATB1 does not affect CTCF occupancy but significantly reduces the retention of CTCF in the nuclear matrix. Collectively, our data show that SATB1 contributes to 3D genome organization by constraining chromatin topology surrounding CTCF-binding sites.
Additional Links: PMID-37000624
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid37000624,
year = {2023},
author = {Wang, B and Ji, L and Bian, Q},
title = {SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites.},
journal = {Cell reports},
volume = {42},
number = {4},
pages = {112323},
doi = {10.1016/j.celrep.2023.112323},
pmid = {37000624},
issn = {2211-1247},
abstract = {Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in spatial genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells leads to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple levels, including compartments, topologically associating domains, and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 leads to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical regulators of T cell activation. The loss of SATB1 does not affect CTCF occupancy but significantly reduces the retention of CTCF in the nuclear matrix. Collectively, our data show that SATB1 contributes to 3D genome organization by constraining chromatin topology surrounding CTCF-binding sites.},
}
RevDate: 2023-03-30
Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.
Molecular cell pii:S1097-2765(23)00166-1 [Epub ahead of print].
Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.
Additional Links: PMID-36996812
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36996812,
year = {2023},
author = {Chen, LF and Long, HK and Park, M and Swigut, T and Boettiger, AN and Wysocka, J},
title = {Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2023.03.009},
pmid = {36996812},
issn = {1097-4164},
abstract = {Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.},
}
RevDate: 2023-03-29
Topologically associating domains in the POLLED region are the same for Angus- and Brahman-specific Hi-C reads from F1 hybrid fetal tissue.
Animal genetics [Epub ahead of print].
Horns, a form of headgear carried by Bovidae, have ethical and economic implications for ruminant production species such as cattle and goats. Hornless (polled) individuals are preferred. In cattle, four genetic variants (Celtic, Friesian, Mongolian and Guarani) are associated with the polled phenotype, which are clustered in a 300-kb region on chromosome 1. As the variants are intergenic, the functional effect is unknown. The aim of this study was to determine if the POLLED variants affect chromatin structure or disrupt enhancers using publicly available data. Topologically associating domains (TADs) were analyzed using Angus- and Brahman-specific Hi-C reads from lung tissue of an Angus (Celtic allele) cross Brahman (horned) fetus. Predicted bovine enhancers and chromatin immunoprecipitation sequencing peaks for histone modifications associated with enhancers (H3K27ac and H3K4me1) were mapped to the POLLED region. TADs analyzed from Angus- and Brahman-specific Hi-C reads were the same, therefore, the Celtic variant does not appear to affect this level of chromatin structure. The Celtic variant is located in a different TAD from the Friesian, Mongolian, and Guarani variants. Predicted enhancers and histone modifications overlapped with the Guarani and Friesian variants but not the Celtic or Mongolian variants. This study provides insight into the mechanisms of the POLLED variants for disrupting horn development. These results should be validated using data produced from the horn bud region of horned and polled bovine fetuses.
Additional Links: PMID-36990727
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36990727,
year = {2023},
author = {Aldersey, JE and Liu, N and Tearle, R and Low, WY and Breen, J and Williams, JL and Bottema, CDK},
title = {Topologically associating domains in the POLLED region are the same for Angus- and Brahman-specific Hi-C reads from F1 hybrid fetal tissue.},
journal = {Animal genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/age.13322},
pmid = {36990727},
issn = {1365-2052},
abstract = {Horns, a form of headgear carried by Bovidae, have ethical and economic implications for ruminant production species such as cattle and goats. Hornless (polled) individuals are preferred. In cattle, four genetic variants (Celtic, Friesian, Mongolian and Guarani) are associated with the polled phenotype, which are clustered in a 300-kb region on chromosome 1. As the variants are intergenic, the functional effect is unknown. The aim of this study was to determine if the POLLED variants affect chromatin structure or disrupt enhancers using publicly available data. Topologically associating domains (TADs) were analyzed using Angus- and Brahman-specific Hi-C reads from lung tissue of an Angus (Celtic allele) cross Brahman (horned) fetus. Predicted bovine enhancers and chromatin immunoprecipitation sequencing peaks for histone modifications associated with enhancers (H3K27ac and H3K4me1) were mapped to the POLLED region. TADs analyzed from Angus- and Brahman-specific Hi-C reads were the same, therefore, the Celtic variant does not appear to affect this level of chromatin structure. The Celtic variant is located in a different TAD from the Friesian, Mongolian, and Guarani variants. Predicted enhancers and histone modifications overlapped with the Guarani and Friesian variants but not the Celtic or Mongolian variants. This study provides insight into the mechanisms of the POLLED variants for disrupting horn development. These results should be validated using data produced from the horn bud region of horned and polled bovine fetuses.},
}
RevDate: 2023-03-21
Genomic rearrangements and evolutionary changes in 3D chromatin topologies in the cotton tribe (Gossypieae).
BMC biology, 21(1):56.
BACKGROUND: Analysis of the relationship between chromosomal structural variation (synteny breaks) and 3D-chromatin architectural changes among closely related species has the potential to reveal causes and correlates between chromosomal change and chromatin remodeling. Of note, contrary to extensive studies in animal species, the pace and pattern of chromatin architectural changes following the speciation of plants remain unexplored; moreover, there is little exploration of the occurrence of synteny breaks in the context of multiple genome topological hierarchies within the same model species.
RESULTS: Here we used Hi-C and epigenomic analyses to characterize and compare the profiles of hierarchical chromatin architectural features in representative species of the cotton tribe (Gossypieae), including Gossypium arboreum, Gossypium raimondii, and Gossypioides kirkii, which differ with respect to chromosome rearrangements. We found that (i) overall chromatin architectural territories were preserved in Gossypioides and Gossypium, which was reflected in their similar intra-chromosomal contact patterns and spatial chromosomal distributions; (ii) the non-random preferential occurrence of synteny breaks in A compartment significantly associate with the B-to-A compartment switch in syntenic blocks flanking synteny breaks; (iii) synteny changes co-localize with open-chromatin boundaries of topologically associating domains, while TAD stabilization has a greater influence on regulating orthologous expression divergence than do rearrangements; and (iv) rearranged chromosome segments largely maintain ancestral in-cis interactions.
CONCLUSIONS: Our findings provide insights into the non-random occurrence of epigenomic remodeling relative to the genomic landscape and its evolutionary and functional connections to alterations of hierarchical chromatin architecture, on a known evolutionary timescale.
Additional Links: PMID-36941615
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36941615,
year = {2023},
author = {Li, X and Wang, J and Yu, Y and Li, G and Wang, J and Li, C and Zeng, Z and Li, N and Zhang, Z and Dong, Q and Yu, Y and Wang, X and Wang, T and Grover, CE and Wang, B and Liu, B and Wendel, JF and Gong, L},
title = {Genomic rearrangements and evolutionary changes in 3D chromatin topologies in the cotton tribe (Gossypieae).},
journal = {BMC biology},
volume = {21},
number = {1},
pages = {56},
pmid = {36941615},
issn = {1741-7007},
abstract = {BACKGROUND: Analysis of the relationship between chromosomal structural variation (synteny breaks) and 3D-chromatin architectural changes among closely related species has the potential to reveal causes and correlates between chromosomal change and chromatin remodeling. Of note, contrary to extensive studies in animal species, the pace and pattern of chromatin architectural changes following the speciation of plants remain unexplored; moreover, there is little exploration of the occurrence of synteny breaks in the context of multiple genome topological hierarchies within the same model species.
RESULTS: Here we used Hi-C and epigenomic analyses to characterize and compare the profiles of hierarchical chromatin architectural features in representative species of the cotton tribe (Gossypieae), including Gossypium arboreum, Gossypium raimondii, and Gossypioides kirkii, which differ with respect to chromosome rearrangements. We found that (i) overall chromatin architectural territories were preserved in Gossypioides and Gossypium, which was reflected in their similar intra-chromosomal contact patterns and spatial chromosomal distributions; (ii) the non-random preferential occurrence of synteny breaks in A compartment significantly associate with the B-to-A compartment switch in syntenic blocks flanking synteny breaks; (iii) synteny changes co-localize with open-chromatin boundaries of topologically associating domains, while TAD stabilization has a greater influence on regulating orthologous expression divergence than do rearrangements; and (iv) rearranged chromosome segments largely maintain ancestral in-cis interactions.
CONCLUSIONS: Our findings provide insights into the non-random occurrence of epigenomic remodeling relative to the genomic landscape and its evolutionary and functional connections to alterations of hierarchical chromatin architecture, on a known evolutionary timescale.},
}
RevDate: 2023-03-14
Heterochromatin rewiring and domain disruption-mediated chromatin compaction during erythropoiesis.
Nature structural & molecular biology [Epub ahead of print].
Mammalian erythropoiesis involves progressive chromatin compaction and subsequent enucleation in terminal differentiation, but the mechanisms underlying the three-dimensional chromatin reorganization remain obscure. Here, we systematically analyze the higher-order chromatin in purified populations of primary human erythroblasts. Our results reveal that heterochromatin regions undergo substantial compression, with H3K9me3 markers relocalizing to the nuclear periphery and forming a significant number of long-range interactions, and that ~58% of the topologically associating domain (TAD) boundaries are disrupted, while certain TADs enriched for markers of the active transcription state and erythroid master regulators, GATA1 and KLF1, are selectively maintained during terminal erythropoiesis. Finally, we demonstrate that GATA1 is involved in safeguarding selected essential chromatin domains during terminal erythropoiesis. Our study therefore delineates the molecular characteristics of a development-driven chromatin compaction process, which reveals transcription competence as a key indicator of the selected domain maintenance to ensure appropriate gene expression during the extreme compaction of chromatin.
Additional Links: PMID-36914797
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36914797,
year = {2023},
author = {Li, D and Wu, F and Zhou, S and Huang, XJ and Lee, HY},
title = {Heterochromatin rewiring and domain disruption-mediated chromatin compaction during erythropoiesis.},
journal = {Nature structural & molecular biology},
volume = {},
number = {},
pages = {},
pmid = {36914797},
issn = {1545-9985},
abstract = {Mammalian erythropoiesis involves progressive chromatin compaction and subsequent enucleation in terminal differentiation, but the mechanisms underlying the three-dimensional chromatin reorganization remain obscure. Here, we systematically analyze the higher-order chromatin in purified populations of primary human erythroblasts. Our results reveal that heterochromatin regions undergo substantial compression, with H3K9me3 markers relocalizing to the nuclear periphery and forming a significant number of long-range interactions, and that ~58% of the topologically associating domain (TAD) boundaries are disrupted, while certain TADs enriched for markers of the active transcription state and erythroid master regulators, GATA1 and KLF1, are selectively maintained during terminal erythropoiesis. Finally, we demonstrate that GATA1 is involved in safeguarding selected essential chromatin domains during terminal erythropoiesis. Our study therefore delineates the molecular characteristics of a development-driven chromatin compaction process, which reveals transcription competence as a key indicator of the selected domain maintenance to ensure appropriate gene expression during the extreme compaction of chromatin.},
}
RevDate: 2023-03-09
Defining the separation landscape of topological domains for decoding consensus domain organization of 3D genome.
Genome research pii:gr.277187.122 [Epub ahead of print].
Topologically associating domains (TADs) have emerged as basic structural and functional units of genome organization, and have been determined by many computational methods from Hi-C contact maps. However, the TADs obtained by different methods vary greatly, which makes the accurate determination of TADs a challenging issue and hinders subsequent biological analyses about their organization and functions. Obvious inconsistencies among the TADs identified by different methods indeed make the statistical and biological properties of TADs overly depend on the method we chose rather than on the data. To this end, we employ the consensus structural information captured by these methods to define the TAD separation landscape for decoding the consensus domain organization of the 3D genome. We demonstrate that the TAD separation landscape could be used to compare domain boundaries across multiple cell types for discovering conserved and divergent topological structures, decipher three types of boundary regions with diverse biological features, and identify Consensus TADs (ConsTADs). We illustrate that these analyses could deepen our understanding of the relationships between the topological domains and chromatin states, gene expression, and DNA replication timing.
Additional Links: PMID-36894325
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36894325,
year = {2023},
author = {Dang, D and Zhang, SW and Duan, R and Zhang, S},
title = {Defining the separation landscape of topological domains for decoding consensus domain organization of 3D genome.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.277187.122},
pmid = {36894325},
issn = {1549-5469},
abstract = {Topologically associating domains (TADs) have emerged as basic structural and functional units of genome organization, and have been determined by many computational methods from Hi-C contact maps. However, the TADs obtained by different methods vary greatly, which makes the accurate determination of TADs a challenging issue and hinders subsequent biological analyses about their organization and functions. Obvious inconsistencies among the TADs identified by different methods indeed make the statistical and biological properties of TADs overly depend on the method we chose rather than on the data. To this end, we employ the consensus structural information captured by these methods to define the TAD separation landscape for decoding the consensus domain organization of the 3D genome. We demonstrate that the TAD separation landscape could be used to compare domain boundaries across multiple cell types for discovering conserved and divergent topological structures, decipher three types of boundary regions with diverse biological features, and identify Consensus TADs (ConsTADs). We illustrate that these analyses could deepen our understanding of the relationships between the topological domains and chromatin states, gene expression, and DNA replication timing.},
}
RevDate: 2023-03-03
Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.
Genome biology, 24(1):40.
BACKGROUND: There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available.
RESULTS: We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs).
CONCLUSIONS: This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.
Additional Links: PMID-36869353
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36869353,
year = {2023},
author = {Richer, S and Tian, Y and Schoenfelder, S and Hurst, L and Murrell, A and Pisignano, G},
title = {Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {40},
pmid = {36869353},
issn = {1474-760X},
support = {MR/P000711/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available.
RESULTS: We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs).
CONCLUSIONS: This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.},
}
RevDate: 2023-02-26
The role of loop extrusion in enhancer-mediated gene activation.
Current opinion in genetics & development, 79:102022 pii:S0959-437X(23)00002-3 [Epub ahead of print].
Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters in three-dimensional (3D) chromatin structures. Despite advances in our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers and promoters are controlled in this 3D context. In this review, we give an overview of recent evidence that shows that a process of loop extrusion plays an important role in the regulation of enhancer-promoter communication and discuss recent insights into the molecular mechanism by which loop extrusion contributes to enhancer-mediated gene activation.
Additional Links: PMID-36842325
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36842325,
year = {2023},
author = {Karpinska, MA and Oudelaar, AM},
title = {The role of loop extrusion in enhancer-mediated gene activation.},
journal = {Current opinion in genetics & development},
volume = {79},
number = {},
pages = {102022},
doi = {10.1016/j.gde.2023.102022},
pmid = {36842325},
issn = {1879-0380},
abstract = {Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters in three-dimensional (3D) chromatin structures. Despite advances in our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers and promoters are controlled in this 3D context. In this review, we give an overview of recent evidence that shows that a process of loop extrusion plays an important role in the regulation of enhancer-promoter communication and discuss recent insights into the molecular mechanism by which loop extrusion contributes to enhancer-mediated gene activation.},
}
RevDate: 2023-02-17
Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.
Science advances, 9(7):eabo1360.
Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer-containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.
Additional Links: PMID-36800432
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36800432,
year = {2023},
author = {Zhao, Y and Ding, Y and He, L and Zhou, Q and Chen, X and Li, Y and Alfonsi, MV and Wu, Z and Sun, H and Wang, H},
title = {Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.},
journal = {Science advances},
volume = {9},
number = {7},
pages = {eabo1360},
doi = {10.1126/sciadv.abo1360},
pmid = {36800432},
issn = {2375-2548},
abstract = {Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer-containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.},
}
RevDate: 2023-02-09
HiConfidence: a novel approach uncovering the biological signal in Hi-C data affected by technical biases.
Briefings in bioinformatics pii:7033301 [Epub ahead of print].
The chromatin interaction assays, particularly Hi-C, enable detailed studies of genome architecture in multiple organisms and model systems, resulting in a deeper understanding of gene expression regulation mechanisms mediated by epigenetics. However, the analysis and interpretation of Hi-C data remain challenging due to technical biases, limiting direct comparisons of datasets obtained in different experiments and laboratories. As a result, removing biases from Hi-C-generated chromatin contact matrices is a critical data analysis step. Our novel approach, HiConfidence, eliminates biases from the Hi-C data by weighing chromatin contacts according to their consistency between replicates so that low-quality replicates do not substantially influence the result. The algorithm is effective for the analysis of global changes in chromatin structures such as compartments and topologically associating domains. We apply the HiConfidence approach to several Hi-C datasets with significant technical biases, that could not be analyzed effectively using existing methods, and obtain meaningful biological conclusions. In particular, HiConfidence aids in the study of how changes in histone acetylation pattern affect chromatin organization in Drosophila melanogaster S2 cells. The method is freely available at GitHub: https://github.com/victorykobets/HiConfidence.
Additional Links: PMID-36759336
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36759336,
year = {2023},
author = {Kobets, VA and Ulianov, SV and Galitsyna, AA and Doronin, SA and Mikhaleva, EA and Gelfand, MS and Shevelyov, YY and Razin, SV and Khrameeva, EE},
title = {HiConfidence: a novel approach uncovering the biological signal in Hi-C data affected by technical biases.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad044},
pmid = {36759336},
issn = {1477-4054},
abstract = {The chromatin interaction assays, particularly Hi-C, enable detailed studies of genome architecture in multiple organisms and model systems, resulting in a deeper understanding of gene expression regulation mechanisms mediated by epigenetics. However, the analysis and interpretation of Hi-C data remain challenging due to technical biases, limiting direct comparisons of datasets obtained in different experiments and laboratories. As a result, removing biases from Hi-C-generated chromatin contact matrices is a critical data analysis step. Our novel approach, HiConfidence, eliminates biases from the Hi-C data by weighing chromatin contacts according to their consistency between replicates so that low-quality replicates do not substantially influence the result. The algorithm is effective for the analysis of global changes in chromatin structures such as compartments and topologically associating domains. We apply the HiConfidence approach to several Hi-C datasets with significant technical biases, that could not be analyzed effectively using existing methods, and obtain meaningful biological conclusions. In particular, HiConfidence aids in the study of how changes in histone acetylation pattern affect chromatin organization in Drosophila melanogaster S2 cells. The method is freely available at GitHub: https://github.com/victorykobets/HiConfidence.},
}
RevDate: 2023-02-09
CmpDate: 2023-02-09
Hi-C analysis of genomic contacts revealed karyotype abnormalities in chicken HD3 cell line.
BMC genomics, 24(1):66.
BACKGROUND: Karyotype abnormalities are frequent in immortalized continuous cell lines either transformed or derived from primary tumors. Chromosomal rearrangements can cause dramatic changes in gene expression and affect cellular phenotype and behavior during in vitro culture. Structural variations of chromosomes in many continuous mammalian cell lines are well documented, but chromosome aberrations in cell lines from other vertebrate models often remain understudied. The chicken LSCC-HD3 cell line (HD3), generated from erythroid precursors, was used as an avian model for erythroid differentiation and lineage-specific gene expression. However, karyotype abnormalities in the HD3 cell line were not assessed. In the present study, we applied high-throughput chromosome conformation capture to analyze 3D genome organization and to detect chromosome rearrangements in the HD3 cell line.
RESULTS: We obtained Hi-C maps of genomic interactions for the HD3 cell line and compared A/B compartments and topologically associating domains between HD3 and several other cell types. By analysis of contact patterns in the Hi-C maps of HD3 cells, we identified more than 25 interchromosomal translocations of regions ≥ 200 kb on both micro- and macrochromosomes. We classified most of the observed translocations as unbalanced, leading to the formation of heteromorphic chromosomes. In many cases of microchromosome rearrangements, an entire microchromosome together with other macro- and microchromosomes participated in the emergence of a derivative chromosome, resembling "chromosomal fusions'' between acrocentric microchromosomes. Intrachromosomal inversions, deletions and duplications were also detected in HD3 cells. Several of the identified simple and complex chromosomal rearrangements, such as between GGA2 and GGA1qter; GGA5, GGA4p and GGA7p; GGA4q, GGA6 and GGA19; and duplication of the sex chromosome GGAW, were confirmed by FISH.
CONCLUSIONS: In the erythroid progenitor HD3 cell line, in contrast to mature and immature erythrocytes, the genome is organized into distinct topologically associating domains. The HD3 cell line has a severely rearranged karyotype with most of the chromosomes engaged in translocations and can be used in studies of genome structure-function relationships. Hi-C proved to be a reliable tool for simultaneous assessment of the spatial genome organization and chromosomal aberrations in karyotypes of birds with a large number of microchromosomes.
Additional Links: PMID-36750787
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36750787,
year = {2023},
author = {Maslova, A and Plotnikov, V and Nuriddinov, M and Gridina, M and Fishman, V and Krasikova, A},
title = {Hi-C analysis of genomic contacts revealed karyotype abnormalities in chicken HD3 cell line.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {66},
pmid = {36750787},
issn = {1471-2164},
mesh = {Animals ; *Chickens/genetics ; Karyotype ; *Genomics ; Sex Chromosomes ; Chromosome Aberrations ; Mammals/genetics ; },
abstract = {BACKGROUND: Karyotype abnormalities are frequent in immortalized continuous cell lines either transformed or derived from primary tumors. Chromosomal rearrangements can cause dramatic changes in gene expression and affect cellular phenotype and behavior during in vitro culture. Structural variations of chromosomes in many continuous mammalian cell lines are well documented, but chromosome aberrations in cell lines from other vertebrate models often remain understudied. The chicken LSCC-HD3 cell line (HD3), generated from erythroid precursors, was used as an avian model for erythroid differentiation and lineage-specific gene expression. However, karyotype abnormalities in the HD3 cell line were not assessed. In the present study, we applied high-throughput chromosome conformation capture to analyze 3D genome organization and to detect chromosome rearrangements in the HD3 cell line.
RESULTS: We obtained Hi-C maps of genomic interactions for the HD3 cell line and compared A/B compartments and topologically associating domains between HD3 and several other cell types. By analysis of contact patterns in the Hi-C maps of HD3 cells, we identified more than 25 interchromosomal translocations of regions ≥ 200 kb on both micro- and macrochromosomes. We classified most of the observed translocations as unbalanced, leading to the formation of heteromorphic chromosomes. In many cases of microchromosome rearrangements, an entire microchromosome together with other macro- and microchromosomes participated in the emergence of a derivative chromosome, resembling "chromosomal fusions'' between acrocentric microchromosomes. Intrachromosomal inversions, deletions and duplications were also detected in HD3 cells. Several of the identified simple and complex chromosomal rearrangements, such as between GGA2 and GGA1qter; GGA5, GGA4p and GGA7p; GGA4q, GGA6 and GGA19; and duplication of the sex chromosome GGAW, were confirmed by FISH.
CONCLUSIONS: In the erythroid progenitor HD3 cell line, in contrast to mature and immature erythrocytes, the genome is organized into distinct topologically associating domains. The HD3 cell line has a severely rearranged karyotype with most of the chromosomes engaged in translocations and can be used in studies of genome structure-function relationships. Hi-C proved to be a reliable tool for simultaneous assessment of the spatial genome organization and chromosomal aberrations in karyotypes of birds with a large number of microchromosomes.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Animals
*Chickens/genetics
Karyotype
*Genomics
Sex Chromosomes
Chromosome Aberrations
Mammals/genetics
RevDate: 2023-02-07
CmpDate: 2023-02-07
Capturing Chromosome Conformation Across Length Scales.
Journal of visualized experiments : JoVE.
Chromosome conformation capture (3C) is used to detect three-dimensional chromatin interactions. Typically, chemical crosslinking with formaldehyde (FA) is used to fix chromatin interactions. Then, chromatin digestion with a restriction enzyme and subsequent religation of fragment ends converts three-dimensional (3D) proximity into unique ligation products. Finally, after reversal of crosslinks, protein removal, and DNA isolation, DNA is sheared and prepared for high-throughput sequencing. The frequency of proximity ligation of pairs of loci is a measure of the frequency of their colocalization in three-dimensional space in a cell population. A sequenced Hi-C library provides genome-wide information on interaction frequencies between all pairs of loci. The resolution and precision of Hi-C relies on efficient crosslinking that maintains chromatin contacts and frequent and uniform fragmentation of the chromatin. This paper describes an improved in situ Hi-C protocol, Hi-C 3.0, that increases the efficiency of crosslinking by combining two crosslinkers (formaldehyde [FA] and disuccinimidyl glutarate [DSG]), followed by finer digestion using two restriction enzymes (DpnII and DdeI). Hi-C 3.0 is a single protocol for the accurate quantification of genome folding features at smaller scales such as loops and topologically associating domains (TADs), as well as features at larger nucleus-wide scales such as compartments.
Additional Links: PMID-36744801
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36744801,
year = {2023},
author = {Yang, L and Akgol Oksuz, B and Dekker, J and Gibcus, JH},
title = {Capturing Chromosome Conformation Across Length Scales.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {191},
pages = {},
doi = {10.3791/64001},
pmid = {36744801},
issn = {1940-087X},
mesh = {*Chromosomes/genetics/metabolism ; *Chromatin/genetics ; DNA/genetics/chemistry ; Cell Nucleus/metabolism ; DNA Restriction Enzymes/metabolism ; Formaldehyde/chemistry ; Nucleic Acid Conformation ; },
abstract = {Chromosome conformation capture (3C) is used to detect three-dimensional chromatin interactions. Typically, chemical crosslinking with formaldehyde (FA) is used to fix chromatin interactions. Then, chromatin digestion with a restriction enzyme and subsequent religation of fragment ends converts three-dimensional (3D) proximity into unique ligation products. Finally, after reversal of crosslinks, protein removal, and DNA isolation, DNA is sheared and prepared for high-throughput sequencing. The frequency of proximity ligation of pairs of loci is a measure of the frequency of their colocalization in three-dimensional space in a cell population. A sequenced Hi-C library provides genome-wide information on interaction frequencies between all pairs of loci. The resolution and precision of Hi-C relies on efficient crosslinking that maintains chromatin contacts and frequent and uniform fragmentation of the chromatin. This paper describes an improved in situ Hi-C protocol, Hi-C 3.0, that increases the efficiency of crosslinking by combining two crosslinkers (formaldehyde [FA] and disuccinimidyl glutarate [DSG]), followed by finer digestion using two restriction enzymes (DpnII and DdeI). Hi-C 3.0 is a single protocol for the accurate quantification of genome folding features at smaller scales such as loops and topologically associating domains (TADs), as well as features at larger nucleus-wide scales such as compartments.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
*Chromosomes/genetics/metabolism
*Chromatin/genetics
DNA/genetics/chemistry
Cell Nucleus/metabolism
DNA Restriction Enzymes/metabolism
Formaldehyde/chemistry
Nucleic Acid Conformation
RevDate: 2023-02-05
The epigenetic landscape of oligodendrocyte lineage cells.
Annals of the New York Academy of Sciences [Epub ahead of print].
The epigenetic landscape of oligodendrocyte lineage cells refers to the cell-specific modifications of DNA, chromatin, and RNA that define a unique gene expression pattern of functionally specialized cells. Here, we focus on the epigenetic changes occurring as progenitors differentiate into myelin-forming cells and respond to the local environment. First, modifications of DNA, RNA, nucleosomal histones, key principles of chromatin organization, topologically associating domains, and local remodeling will be reviewed. Then, the relationship between epigenetic modulators and RNA processing will be explored. Finally, the reciprocal relationship between the epigenome as a determinant of the mechanical properties of cell nuclei and the target of mechanotransduction will be discussed. The overall goal is to provide an interpretative key on how epigenetic changes may account for the heterogeneity of the transcriptional profiles identified in this lineage.
Additional Links: PMID-36740586
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36740586,
year = {2023},
author = {Selcen, I and Prentice, E and Casaccia, P},
title = {The epigenetic landscape of oligodendrocyte lineage cells.},
journal = {Annals of the New York Academy of Sciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/nyas.14959},
pmid = {36740586},
issn = {1749-6632},
abstract = {The epigenetic landscape of oligodendrocyte lineage cells refers to the cell-specific modifications of DNA, chromatin, and RNA that define a unique gene expression pattern of functionally specialized cells. Here, we focus on the epigenetic changes occurring as progenitors differentiate into myelin-forming cells and respond to the local environment. First, modifications of DNA, RNA, nucleosomal histones, key principles of chromatin organization, topologically associating domains, and local remodeling will be reviewed. Then, the relationship between epigenetic modulators and RNA processing will be explored. Finally, the reciprocal relationship between the epigenome as a determinant of the mechanical properties of cell nuclei and the target of mechanotransduction will be discussed. The overall goal is to provide an interpretative key on how epigenetic changes may account for the heterogeneity of the transcriptional profiles identified in this lineage.},
}
RevDate: 2023-02-03
A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination.
Molecular cell pii:S1097-2765(23)00037-0 [Epub ahead of print].
Interactions between transcription and cohesin-mediated loop extrusion can influence 3D chromatin architecture. However, their relevance in biology is unclear. Here, we report a direct role for such interactions in the mechanism of antibody class switch recombination (CSR) at the murine immunoglobulin heavy chain locus (Igh). Using Tri-C to measure higher-order multiway interactions on single alleles, we find that the juxtaposition (synapsis) of transcriptionally active donor and acceptor Igh switch (S) sequences, an essential step in CSR, occurs via the interaction of loop extrusion complexes with a de novo topologically associating domain (TAD) boundary formed via transcriptional activity across S regions. Surprisingly, synapsis occurs predominantly in proximity to the 3' CTCF-binding element (3'CBE) rather than the Igh super-enhancer, suggesting a two-step mechanism whereby transcription of S regions is not topologically coupled to synapsis, as has been previously proposed. Altogether, these insights advance our understanding of how 3D chromatin architecture regulates CSR.
Additional Links: PMID-36736317
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36736317,
year = {2023},
author = {Costea, J and Schoeberl, UE and Malzl, D and von der Linde, M and Fitz, J and Gupta, A and Makharova, M and Goloborodko, A and Pavri, R},
title = {A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2023.01.014},
pmid = {36736317},
issn = {1097-4164},
abstract = {Interactions between transcription and cohesin-mediated loop extrusion can influence 3D chromatin architecture. However, their relevance in biology is unclear. Here, we report a direct role for such interactions in the mechanism of antibody class switch recombination (CSR) at the murine immunoglobulin heavy chain locus (Igh). Using Tri-C to measure higher-order multiway interactions on single alleles, we find that the juxtaposition (synapsis) of transcriptionally active donor and acceptor Igh switch (S) sequences, an essential step in CSR, occurs via the interaction of loop extrusion complexes with a de novo topologically associating domain (TAD) boundary formed via transcriptional activity across S regions. Surprisingly, synapsis occurs predominantly in proximity to the 3' CTCF-binding element (3'CBE) rather than the Igh super-enhancer, suggesting a two-step mechanism whereby transcription of S regions is not topologically coupled to synapsis, as has been previously proposed. Altogether, these insights advance our understanding of how 3D chromatin architecture regulates CSR.},
}
RevDate: 2023-02-09
CmpDate: 2023-02-07
CTCF, BEAF-32, and CP190 are not required for the establishment of TADs in early Drosophila embryos but have locus-specific roles.
Science advances, 9(5):eade1085.
The boundaries of topologically associating domains (TADs) are delimited by insulators and/or active promoters; however, how they are initially established during embryogenesis remains unclear. Here, we examined this during the first hours of Drosophila embryogenesis. DNA-FISH confirms that intra-TAD pairwise proximity is established during zygotic genome activation (ZGA) but with extensive cell-to-cell heterogeneity. Most newly formed boundaries are occupied by combinations of CTCF, BEAF-32, and/or CP190. Depleting each insulator individually from chromatin revealed that TADs can still establish, although with lower insulation, with a subset of boundaries (~10%) being more dependent on specific insulators. Some weakened boundaries have aberrant gene expression due to unconstrained enhancer activity. However, the majority of misexpressed genes have no obvious direct relationship to changes in domain-boundary insulation. Deletion of an active promoter (thereby blocking transcription) at one boundary had a greater impact than deleting the insulator-bound region itself. This suggests that cross-talk between insulators and active promoters and/or transcription might reinforce domain boundary insulation during embryogenesis.
Additional Links: PMID-36735786
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36735786,
year = {2023},
author = {Cavalheiro, GR and Girardot, C and Viales, RR and Pollex, T and Cao, TBN and Lacour, P and Feng, S and Rabinowitz, A and Furlong, EEM},
title = {CTCF, BEAF-32, and CP190 are not required for the establishment of TADs in early Drosophila embryos but have locus-specific roles.},
journal = {Science advances},
volume = {9},
number = {5},
pages = {eade1085},
pmid = {36735786},
issn = {2375-2548},
mesh = {Animals ; *Drosophila/genetics/metabolism ; *Drosophila Proteins/metabolism ; Genome ; Chromatin/genetics ; Chromosomes ; DNA-Binding Proteins/metabolism ; Eye Proteins/genetics/metabolism ; Microtubule-Associated Proteins/metabolism ; Nuclear Proteins/metabolism ; CCCTC-Binding Factor/genetics ; },
abstract = {The boundaries of topologically associating domains (TADs) are delimited by insulators and/or active promoters; however, how they are initially established during embryogenesis remains unclear. Here, we examined this during the first hours of Drosophila embryogenesis. DNA-FISH confirms that intra-TAD pairwise proximity is established during zygotic genome activation (ZGA) but with extensive cell-to-cell heterogeneity. Most newly formed boundaries are occupied by combinations of CTCF, BEAF-32, and/or CP190. Depleting each insulator individually from chromatin revealed that TADs can still establish, although with lower insulation, with a subset of boundaries (~10%) being more dependent on specific insulators. Some weakened boundaries have aberrant gene expression due to unconstrained enhancer activity. However, the majority of misexpressed genes have no obvious direct relationship to changes in domain-boundary insulation. Deletion of an active promoter (thereby blocking transcription) at one boundary had a greater impact than deleting the insulator-bound region itself. This suggests that cross-talk between insulators and active promoters and/or transcription might reinforce domain boundary insulation during embryogenesis.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Animals
*Drosophila/genetics/metabolism
*Drosophila Proteins/metabolism
Genome
Chromatin/genetics
Chromosomes
DNA-Binding Proteins/metabolism
Eye Proteins/genetics/metabolism
Microtubule-Associated Proteins/metabolism
Nuclear Proteins/metabolism
CCCTC-Binding Factor/genetics
RevDate: 2023-02-02
CmpDate: 2023-02-02
T-REX17 is a transiently expressed non-coding RNA essential for human endoderm formation.
eLife, 12:.
Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.
Additional Links: PMID-36719724
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36719724,
year = {2023},
author = {Landshammer, A and Bolondi, A and Kretzmer, H and Much, C and Buschow, R and Rose, A and Wu, HJ and Mackowiak, SD and Braendl, B and Giesselmann, P and Tornisiello, R and Parsi, KM and Huey, J and Mielke, T and Meierhofer, D and Maehr, R and Hnisz, D and Michor, F and Rinn, JL and Meissner, A},
title = {T-REX17 is a transiently expressed non-coding RNA essential for human endoderm formation.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {36719724},
issn = {2050-084X},
mesh = {Pregnancy ; Female ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; Epithelial-Mesenchymal Transition ; Endoderm ; Gene Expression Regulation, Developmental ; SOXF Transcription Factors/genetics/metabolism ; Cell Differentiation/genetics ; },
abstract = {Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Pregnancy
Female
Humans
*RNA, Long Noncoding/genetics/metabolism
Epithelial-Mesenchymal Transition
Endoderm
Gene Expression Regulation, Developmental
SOXF Transcription Factors/genetics/metabolism
Cell Differentiation/genetics
RevDate: 2023-02-03
CmpDate: 2023-02-03
Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens.
Nature immunology, 24(2):320-336.
Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.
Additional Links: PMID-36717722
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36717722,
year = {2023},
author = {Barajas-Mora, EM and Lee, L and Lu, H and Valderrama, JA and Bjanes, E and Nizet, V and Feeney, AJ and Hu, M and Murre, C},
title = {Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens.},
journal = {Nature immunology},
volume = {24},
number = {2},
pages = {320-336},
pmid = {36717722},
issn = {1529-2916},
mesh = {Mice ; Animals ; *Chromatin/genetics ; Immunoglobulin Variable Region/genetics ; Immunoglobulin kappa-Chains/genetics ; *Methicillin-Resistant Staphylococcus aureus/genetics ; B-Lymphocytes ; Epigenesis, Genetic ; },
abstract = {Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Mice
Animals
*Chromatin/genetics
Immunoglobulin Variable Region/genetics
Immunoglobulin kappa-Chains/genetics
*Methicillin-Resistant Staphylococcus aureus/genetics
B-Lymphocytes
Epigenesis, Genetic
RevDate: 2023-01-28
Chromatin landscape governing murine epidermal differentiation.
The Journal of investigative dermatology pii:S0022-202X(23)00017-9 [Epub ahead of print].
Chromatin landscape and regulatory networks are determinant in lineage specification and differentiation. To define the temporospatial differentiation axis in murine epidermal cells in vivo, we generated datasets profiling expression dynamics (RNA-Seq), chromatin accessibility (ATAC-Seq), architecture (Hi-C), and histone modifications (ChIP-Seq) in the epidermis. We show that many differentially regulated genes are suppressed during the differentiation process, with super-enhancers (SEs) controlling differentiation-specific epigenomic changes. Our data shows the relevance of the Dlx/Klf/Grhl combinatorial regulatory network in maintaining correct temporospatial gene expression during epidermal differentiation. We determined differential open compartments, topologically associating domain (TAD) score and looping in the Basal cell (B) and Suprabasal cell (SB) epidermal fractions, with the evolutionarily conserved Epidermal Differentiation Complex (EDC) region showing distinct SB-specific TAD and loop formation that coincided with SE sites. Overall, our study provides a global genome-wide resource of chromatin dynamics that define unrecognized regulatory networks and the epigenetic control of Dlx3-bound SE elements during epidermal differentiation.
Additional Links: PMID-36708949
Publisher:
PubMed:
Citation:
show bibtex listing
hide bibtex listing
@article {pmid36708949,
year = {2023},
author = {Nayak, S and Jiang, K and Hope, E and Cross, M and Overmiller, A and Naz, F and Worrell, S and Bajpai, D and Hasneen, K and Brooks, SR and Dell'Orso, S and Morasso, MI},
title = {Chromatin landscape governing murine epidermal differentiation.},
journal = {The Journal of investigative dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jid.2022.12.020},
pmid = {36708949},
issn = {1523-1747},
abstract = {Chromatin landscape and regulatory networks are determinant in lineage specification and differentiation. To define the temporospatial differentiation axis in murine epidermal cells in vivo, we generated datasets profiling expression dynamics (RNA-Seq), chromatin accessibility (ATAC-Seq), architecture (Hi-C), and histone modifications (ChIP-Seq) in the epidermis. We show that many differentially regulated genes are suppressed during the differentiation process, with super-enhancers (SEs) controlling differentiation-specific epigenomic changes. Our data shows the relevance of the Dlx/Klf/Grhl combinatorial regulatory network in maintaining correct temporospatial gene expression during epidermal differentiation. We determined differential open compartments, topologically associating domain (TAD) score and looping in the Basal cell (B) and Suprabasal cell (SB) epidermal fractions, with the evolutionarily conserved Epidermal Differentiation Complex (EDC) region showing distinct SB-specific TAD and loop formation that coincided with SE sites. Overall, our study provides a global genome-wide resource of chromatin dynamics that define unrecognized regulatory networks and the epigenetic control of Dlx3-bound SE elements during epidermal differentiation.},
}
▼ ▼ LOAD NEXT 100 CITATIONS
ESP Quick Facts
ESP Origins
In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.
ESP Support
In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.
ESP Rationale
Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.
ESP Goal
In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.
ESP Usage
Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.
ESP Content
When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.
ESP Help
Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.
ESP Plans
With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.
ESP Picks from Around the Web (updated 07 JUL 2018 )
Old Science
Weird Science
Treating Disease with Fecal Transplantation
Fossils of miniature humans (hobbits) discovered in Indonesia
Paleontology
Dinosaur tail, complete with feathers, found preserved in amber.
Astronomy
Mysterious fast radio burst (FRB) detected in the distant universe.
Big Data & Informatics
Big Data: Buzzword or Big Deal?
Hacking the genome: Identifying anonymized human subjects using publicly available data.