Comprehensive mapping of long-range interactions reveals folding principles of the human genome.
09 Oct 2009-Science (American Association for the Advancement of Science)-Vol. 326, Iss: 5950, pp 289-293
TL;DR: Hi-C is described, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing and demonstrates the power of Hi-C to map the dynamic conformations of entire genomes.
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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28 Jul 2005
TL;DR: PfPMP1）与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。
18,940 citations
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.
5,945 citations
Cites background or methods or result from "Comprehensive mapping of long-range..."
...In our earlier experiments at 1 Mb map resolution (Lieberman-Aiden et al., 2009), we saw large squares of enhanced contact frequency tiling the diagonal of the contact matrices....
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...C showed strong consistency between our loop calls and all six previously published Hi-C experiments in lymphoblastoid cell lines (Lieberman-Aiden et al., 2009; Kalhor et al., 2012) (Figure 3D; Data S2, I.E; Table S6)....
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...Dilution Hi-C was performed as in Lieberman-Aiden et al. (2009)....
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...(C) We compare our map of chromosome 7 in GM12878 (last column) to earlier Hi-Cmaps: Lieberman-Aiden et al. (2009), Kalhor et al. (2012), and Jin et al. (2013)....
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...To interrogate all loci at once, we developed Hi-C, which combines DNA proximity ligation with high-throughput sequencing in a genome-wide fashion (Lieberman-Aiden et al., 2009)....
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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.
Abstract: The 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.
5,774 citations
Massachusetts Institute of Technology1, Broad Institute2, University of California, Los Angeles3, University of British Columbia4, Baylor College of Medicine5, Howard Hughes Medical Institute6, University of Washington7, Ludwig Institute for Cancer Research8, University of California, San Francisco9, University of Connecticut10, University of Zagreb11, University of Texas at Austin12, Washington University in St. Louis13, University of Queensland14, Harvard University15, Cold Spring Harbor Laboratory16, University of Southern California17, University of California, Santa Cruz18, Simon Fraser University19, Morgridge Institute for Research20, University of Texas at Dallas21, National Institutes of Health22
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.
5,037 citations
01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
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.
4,409 citations
References
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TL;DR: The basic chromatin immunoprecipitation technique is remarkably versatile and has now been used in a wide range of cell types, including budding yeast, fly, and human cells, and it seems likely that many more studies, centered around chromatin structure and protein-DNA interactions in its native setting, will benefit from this technique.
604 citations
TL;DR: Observations indicate that the brown gene is silenced by specific contact with centromeric heterochromatin, providing direct evidence for long-range chromosome interactions and their impact on three-dimensional nuclear architecture, while providing a cohesive explanation for the phenomenon of PEV.
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TL;DR: The role of chromatin insulators in eukaryotic gene regulation has been investigated in this paper, showing that they are active participants in gene regulation in yeast, Drosophila, and vertebrates.
Abstract: Insulators mark the boundaries of chromatin domains by limiting the range of action of enhancers and silencers. Although the properties of insulators have been well studied, their role in vivo has largely been a subject of speculation. Recent results make it possible to ascribe specific and essential functions to the insulators ofDrosophila, yeast, and vertebrates. In some cases, insulator activity can be modulated by nearby regulatory elements, bound cofactors, or covalent modification of the DNA. Not simply passive barriers, insulators are active participants in eukaryotic gene regulation.
395 citations
TL;DR: In this paper, it was shown that the kinetics of collapse of a polymer coil consisting of N segments after an abrupt decrease of temperature is a two-stage process if N >> Ne.
Abstract: It is shown that the kinetics of collapse of a polymer coil consisting of N segments after an abrupt decrease of temperature is a two-stage process if N >> Ne. The first stage takes a time ∼ N2 and leads to the peculiar state — crumpled, or fractal, globule. Any part of a chain of any scale is itself a globule in this state ; these parts are segregated from each other in space due to the non-phantomness of a chain. The chain fold in the crumpled globule is a fractal line with fractal dimension 3, equal to the space dimension. The second stage is a chain knotting ; it is realized by means of reptation-like mechanism of motion, takes a time ∼ N3 and is accompanied by an increase of globule density.
394 citations
01 Jan 2001
TL;DR: Not simply passive barriers, insulators are active participants in eukaryotic gene regulation and can be modulated by nearby regulatory elements, bound cofactors, or covalent modification of the DNA.
373 citations