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Journal ArticleDOI

Topological domains in mammalian genomes identified by analysis of chromatin interactions

17 May 2012-Nature (Nature Research)-Vol. 485, Iss: 7398, pp 376-380

TL;DR: It is found that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.

AbstractThe spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.

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Citations
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Journal ArticleDOI
18 Dec 2014-Cell
TL;DR: In situ Hi-C is used to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types, identifying ∼10,000 loops that frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species.
Abstract: We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.

4,386 citations


Cites background or methods or result from "Topological domains in mammalian ge..."

  • ...We found that most peak loci encompass a unique DNA site containing a CTCF-binding motif, to which all three proteins (CTCF, SMC3, and RAD21) were bound (5-fold enrichment)....

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  • ...On the other hand, the domains we observe are much smaller than the TADs (1 Mb) (Dixon et al., 2012) that have been reported in humans and mice on the basis of lower-resolution contact maps....

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  • ...Our in situ Hi-C protocol involves crosslinking cells with formaldehyde, permeabilizing them with nuclei intact, digesting DNA with a suitable 4-cutter restriction enzyme (such as MboI), filling the 50-overhangs while incorporating a biotinylated nucleotide, ligating the resulting blunt-end fragments, shearing the DNA, capturing the biotinylated ligation junctions with streptavidin beads, and analyzing the resulting fragments with paired-end sequencing (Figure 1A)....

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  • ...Because many of our loops demarcate domains, this observation is also consistent with studies suggesting that CTCF delimits structural and regulatory domains (Xie et al., 2007; Cuddapah et al., 2009; Dixon et al., 2012)....

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  • ...(C) Percent of peak loci bound versus fold enrichment for 76 DNA-binding proteins....

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Journal ArticleDOI
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19 Feb 2015-Nature
TL;DR: It is shown that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,169 citations


01 Feb 2015
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

3,734 citations


Journal ArticleDOI
Abstract: The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serve as the template for protein synthesis. The discovery of extensive transcription of large RNA transcripts that do not code for proteins, termed long noncoding RNAs (lncRNAs), provides an important new perspective on the centrality of RNA in gene regulation. Here, we discuss genome-scale strategies to discover and characterize lncRNAs. An emerging theme from multiple model systems is that lncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators and then target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, lncRNAs can function as modular scaffolds to specify higher-order organization in RNP complexes and in chromatin states. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs for proper gene control across all kingdoms of life.

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Journal ArticleDOI
11 Apr 2013-Cell
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Abstract: We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

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02 Aug 2007-Nature
TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.
Abstract: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences Lysine 4 and lysine 9 trimethylation marks imprinting control regions Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations

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"Topological domains in mammalian ge..." refers background in this paper

  • ...mESC H3K36me3, H3K79me2, Oct4, Sox2, Nanog Figure 4, Supplemental Figure 20-22 GSE11724 Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521-33 (2008).(42) mESC H3K9me3 Figure 2, 4 GSE18371 Bilodeau, S....

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  • ...mESC H3K36me3, H3K79me2, Oct4, Sox2, Nanog Figure 4, Supplemental Figure 20-22 GSE11724 Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521-33 (2008).(42) mESC H3K9me3 Figure 2, 4 GSE18371 Bilodeau, S., Kagey, M.H., Frampton, G.M., Rahl, P.B. & Young, R.A. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23, 2484-9 (2009).(43) mESC Jarid2, Jarid1a, Suz12, Ezh2 Supplemental Figure 20-22 GSE18776 Peng, J....

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  • ...mESC H3K36me3, H3K79me2, Oct4, Sox2, Nanog Figure 4, Supplemental Figure 20-22 GSE11724 Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521-33 (2008).(42) mESC H3K9me3 Figure 2, 4 GSE18371 Bilodeau, S., Kagey, M.H., Frampton, G.M., Rahl, P.B. & Young, R.A. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23, 2484-9 (2009).(43) mESC Jarid2, Jarid1a, Suz12, Ezh2 Supplemental Figure 20-22 GSE18776 Peng, J.C. et al. Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139, 1290-302 (2009).(44) mESC PolII Serine 5, PolII Serine 2, NelfA, Ctr9, Spt5 Supplemental Figure 20-22 GSE20530 Rahl, P....

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