scholarly journals Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Bryan J. Matthews ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Genome Organization ◽  
Mouse Liver ◽  
3D Genome ◽  
Chromatin Interactions

scholarly journals Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2020 ◽  
Author(s):  
Bryan J Matthews ◽  
David J Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Binding Sites ◽  
Genome Organization ◽  
Mouse Liver ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
3D Genome ◽  
Chromatin Interactions ◽  
The Impact

Abstract Several thousand sex-differential distal enhancers have been identified in mouse liver; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization and chromatin interactions are unknown. To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were primarily distal to sex-biased genes but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors, and were sometimes found in TADs without sex-biased genes. A substantial subset of sex-biased cohesin-non-CTCF binding sites, but not sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer - promoter interactions are common. Intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer - promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers. Furthermore, sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. These studies elucidate how 3D genome organization impacts sex-biased gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.

scholarly journals Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2020 ◽  
Author(s):  
Bryan J Matthews ◽  
David J Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Binding Sites ◽  
Genome Organization ◽  
Mouse Liver ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
3D Genome ◽  
Chromatin Interactions ◽  
The Impact

Abstract Several thousand sex-differential distal enhancers have been identified in mouse liver; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization and chromatin interactions are unknown. To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were primarily distal to sex-biased genes but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors, and were sometimes found in TADs without sex-biased genes. A substantial subset of sex-biased cohesin-non-CTCF binding sites, but not sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer - promoter interactions are common. Intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer - promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers. Furthermore, sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. These studies elucidate how 3D genome organization impacts sex-biased gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.

scholarly journals Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2020 ◽  
Author(s):  
Bryan J Matthews ◽  
David J Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Binding Sites ◽  
Genome Organization ◽  
Mouse Liver ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
3 Dimensional ◽  
Chromatin Interactions ◽  
The Impact

Abstract Background: Sex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown.Results: To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. Furthermore, intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers.Conclusions: These findings elucidate how 3-dimensional genome organization contributes to sex differences in gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.

scholarly journals Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

2019 ◽  
Author(s):  
Bryan J. Matthews ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Binding Sites ◽  
Genome Organization ◽  
Mouse Liver ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
3 Dimensional ◽  
Chromatin Interactions ◽  
The Impact

AbstractBackgroundSex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown.ResultsTo address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. Furthermore, intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers.ConclusionsThese findings elucidate how 3-dimensional genome organization contributes to sex differences in gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.

scholarly journals The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions

2017 ◽  
Author(s):  
Yanli Wang ◽  
Bo Zhang ◽  
Lijun Zhang ◽  
Lin An ◽  
Jie Xu ◽  
...  
Keyword(s):  
Genome Organization ◽  
Target Genes ◽  
Genome Structure ◽  
Regulatory Elements ◽  
Genomic Region ◽  
Genome Browser ◽  
Chromatin Interaction ◽  
Interaction Data ◽  
3D Genome ◽  
Chromatin Interactions

ABSTRACTRecent advent of 3C-based technologies such as Hi-C and ChIA-PET provides us an opportunity to explore chromatin interactions and 3D genome organization in an unprecedented scale and resolution. However, it remains a challenge to visualize chromatin interaction data due to its size and complexity. Here, we introduce the 3D Genome Browser (http://3dgenome.org), which allows users to conveniently explore both publicly available and their own chromatin interaction data. Users can also seamlessly integrate other “omics” data sets, such as ChIP-Seq and RNA-Seq for the same genomic region, to gain a complete view of both regulatory landscape and 3D genome structure for any given gene. Finally, our browser provides multiple methods to link distal cis-regulatory elements with their potential target genes, including virtual 4C, ChIA-PET, Capture Hi-C and cross-cell-type correlation of proximal and distal DNA hypersensitive sites, and therefore represents a valuable resource for the study of gene regulation in mammalian genomes.

scholarly journals Exploring Mammalian Genome within Phase-Separated Nuclear Bodies: Experimental Methods and Implications for Gene Expression

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1049 ◽  
Author(s):  
Annick Lesne ◽  
Marie-Odile Baudement ◽  
Cosette Rebouissou ◽  
Thierry Forné
Keyword(s):  
Gene Expression ◽  
Self Assembly ◽  
Genome Organization ◽  
Physical Nature ◽  
Mammalian Genome ◽  
Nuclear Bodies ◽  
Control Of Gene Expression ◽  
Chromatin Interactions ◽  
Nuclear Structures ◽  
Genomic Regions

The importance of genome organization at the supranucleosomal scale in the control of gene expression is increasingly recognized today. In mammals, Topologically Associating Domains (TADs) and the active/inactive chromosomal compartments are two of the main nuclear structures that contribute to this organization level. However, recent works reviewed here indicate that, at specific loci, chromatin interactions with nuclear bodies could also be crucial to regulate genome functions, in particular transcription. They moreover suggest that these nuclear bodies are membrane-less organelles dynamically self-assembled and disassembled through mechanisms of phase separation. We have recently developed a novel genome-wide experimental method, High-salt Recovered Sequences sequencing (HRS-seq), which allows the identification of chromatin regions associated with large ribonucleoprotein (RNP) complexes and nuclear bodies. We argue that the physical nature of such RNP complexes and nuclear bodies appears to be central in their ability to promote efficient interactions between distant genomic regions. The development of novel experimental approaches, including our HRS-seq method, is opening new avenues to understand how self-assembly of phase-separated nuclear bodies possibly contributes to mammalian genome organization and gene expression.

scholarly journals The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

2020 ◽  
Author(s):  
Masami Ando-Kuri ◽  
Rodrigo G. Arzate-Mejía ◽  
Jorg Morf ◽  
Jonathan Cairns ◽  
Cesar A. Poot-Hernández ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Liver ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Chromatin Conformation ◽  
Gene Promoters ◽  
Circadian Gene ◽  
Circadian Genes ◽  
Physiological Importance ◽  
3D Genome

SummaryCircadian gene expression is essential for organisms to adjust cellular responses and anticipate daily changes in the environment. In addition to its physiological importance, the clock circuit represents an ideal, temporally resolved, system to study transcription regulation. Here, we analysed changes in spatial mouse liver chromatin conformation using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription in mouse liver. We found circadian topologically associated domains switched assignments to the transcriptionally active, open chromatin compartment and the inactive compartment at different hours of the day while their boundaries stably maintain their structure over time. Individual circadian gene promoters displayed maximal chromatin contacts at times of peak transcriptional output and the expression of circadian genes and contacted transcribed regulatory elements, or other circadian genes, was phase-coherent. Anchor sites of promoter chromatin loops were enriched in binding sites for liver nuclear receptors and transcription factors, some exclusively present in either rhythmic or stable contacts. The circadian 3D chromatin maps provided here identify the scales of chromatin conformation that parallel oscillatory gene expression and protein factors specifically associated with circadian or stable chromatin configurations.

scholarly journals Interplay of pericentromeric genome organization and chromatin landscape regulates the expression of Drosophila melanogaster heterochromatic genes

2019 ◽  
Author(s):  
Parna Saha ◽  
Divya Tej Sowpati ◽  
Ishanee Srivastava ◽  
Rakesh Kumar Mishra
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Genome Organization ◽  
Constitutive Heterochromatin ◽  
Pericentromeric Heterochromatin ◽  
Chromatin Interactions ◽  
Recent Developments ◽  
Epigenetic Code ◽  
Heterochromatic Genes

AbstractTranscription of heterochromatic genes residing within the constitutive heterochromatin is paradoxical to the tenets of the epigenetic code. Drosophila melanogaster heterochromatic genes serve as an excellent model system to understand the mechanisms of their transcriptional regulation. Recent developments in chromatin conformation techniques have revealed that genome organization regulates the transcriptional outputs. Thus, using 5C-seq in S2 cells, we present a detailed characterization of the hierarchical genome organization of Drosophila pericentromeric heterochromatin and its contribution to heterochromatic gene expression. We show that pericentromeric TAD borders are enriched in nuclear Matrix attachment regions while the intra-TAD interactions are mediated by various insulator binding proteins. Heterochromatic genes of similar expression levels cluster into Het TADs which indicates their transcriptional co-regulation. To elucidate how heterochromatic factors, influence the expression of heterochromatic genes, we performed 5C-seq in the HP1a or Su(var)3-9 depleted cells. HP1a or Su(var)3-9 RNAi results in perturbation of global pericentromeric TAD organization but the expression of the heterochromatic genes is minimally affected. Subset of active heterochromatic genes have been shown to have combination of HP1a/H3K9me3 with H3K36me3 at their exons. Interestingly, the knock-down of dMES-4 (H3K36 methyltransferase), downregulates expression of the heterochromatic genes. This indicates that the local chromatin interactions and the combination of heterochromatic factors (HP1a or H3K9me3) along with the H3K36me3 is crucial to drive the expression of heterochromatic genes. Furthermore, dADD1, present near the TSS of the active heterochromatic genes, can bind to both H3K9me3 or HP1a and facilitate the heterochromatic gene expression by regulating the H3K36me3 levels. Therefore, our findings provide mechanistic insights into the interplay of genome organization and chromatin factors at the pericentromeric heterochromatin that regulates Drosophila melanogaster heterochromatic gene expression.

scholarly journals AGO1 in association with NEAT1 lncRNA contributes to nuclear and 3D chromatin architecture in human cells

2019 ◽  
Author(s):  
Muhammad Shuaib ◽  
Krishna Mohan Parsi ◽  
Hideya Kawaji ◽  
Manjula Thimma ◽  
Sabir Abdu Adroub ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Organization ◽  
Global Gene Expression ◽  
Human Cells ◽  
Nuclear Bodies ◽  
Genome Architecture ◽  
Global Changes ◽  
Active Chromatin ◽  
Altered Expression ◽  
3D Genome

AbstractAside from their roles in the cytoplasm, RNA-interference components have been reported to localize also in the nucleus of human cells. In particular, AGO1 associates with active chromatin and appears to influence global gene expression. However, the mechanistic aspects remain elusive. Here, we identify AGO1 as a paraspeckle component that in combination with the NEAT1 lncRNA maintains 3D genome architecture. We demonstrate that AGO1 interacts with NEAT1 lncRNA and its depletion affects NEAT1 expression and the formation of paraspeckles. By Hi-C analysis in AGO1 knockdown cells, we observed global changes in chromatin organization, including TADs configuration, and A/B compartment mixing. Consistently, distinct groups of genes located within the differential interacting loci showed altered expression upon AGO1 depletion. NEAT1 knockout cells displayed similar changes in TADs and higher-order A/B compartmentalization. We propose that AGO1 in association with NEAT1 lncRNA can act as a scaffold that bridges chromatin and nuclear bodies to regulate genome organization and gene expression in human cells.

scholarly journals Probing multi-way chromatin interaction with hypergraph representation learning

2020 ◽  
Author(s):  
Ruochi Zhang ◽  
Jian Ma
Keyword(s):  
Genome Organization ◽  
Representation Learning ◽  
Higher Order ◽  
Computational Method ◽  
Chromatin Interaction ◽  
Interaction Data ◽  
3D Genome ◽  
Chromatin Interactions ◽  
Single Nucleus ◽  
And Function

AbstractAdvances in high-throughput mapping of 3D genome organization have enabled genome-wide characterization of chromatin interactions. However, proximity ligation based mapping approaches for pairwise chromatin interaction such as Hi-C cannot capture multi-way interactions, which are informative to delineate higher-order genome organization and gene regulation mechanisms at single-nucleus resolution. The very recent development of ligation-free chromatin interaction mapping methods such as SPRITE and ChIA-Drop has offered new opportunities to uncover simultaneous interactions involving multiple genomic loci within the same nuclei. Unfortunately, methods for analyzing multi-way chromatin interaction data are significantly underexplored. Here we develop a new computational method, called MATCHA, based on hypergraph representation learning where multi-way chromatin interactions are represented as hyperedges. Applications to SPRITE and ChIA-Drop data suggest that MATCHA is effective to denoise the data and make de novo predictions of multi-way chromatin interactions, reducing the potential false positives and false negatives from the original data. We also show that MATCHA is able to distinguish between multi-way interaction in a single nucleus and combination of pairwise interactions in a cell population. In addition, the embeddings from MATCHA reflect 3D genome spatial localization and function. MATCHA provides a promising framework to significantly improve the analysis of multi-way chromatin interaction data and has the potential to offer unique insights into higher-order chromosome organization and function.

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