scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Topological domains in mammalian genomes identified by analysis of chromatin interactions

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.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: The data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner, and points to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-ob obesity effects.
Abstract: BackgroundGenomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive MethodsWe examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients ResultsOur data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a pot

1,097 citations

Journal ArticleDOI
TL;DR: A brief history of gene-editing tools is presented and the wide range of CRISPR-based genome-targeting tools are described, to conclude with future directions and the broader impact ofCRISPR technologies.
Abstract: CRISPR is becoming an indispensable tool in biological research. Once known as the bacterial immune system against invading viruses, the programmable capacity of the Cas9 enzyme is now revolutionizing diverse fields of medical research, biotechnology, and agriculture. CRISPR-Cas9 is no longer just a gene-editing tool; the application areas of catalytically impaired inactive Cas9, including gene regulation, epigenetic editing, chromatin engineering, and imaging, now exceed the gene-editing functionality of WT Cas9. Here, we will present a brief history of gene-editing tools and describe the wide range of CRISPR-based genome-targeting tools. We will conclude with future directions and the broader impact of CRISPR technologies.

1,092 citations

Journal ArticleDOI
06 Jun 2013-Cell
TL;DR: It is concluded that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.

1,092 citations


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

  • ...Megabase-scale TADs appear to be constant between mammalian cell types and conserved across species (Dixon et al., 2012; Nora et al., 2012)....

    [...]

  • ...More recently, technologies for genome-wide mapping of chromatin architecture have been described, but comprehensive detection comes at the expense of resolution for mammalian genomes (Hi-C) (Dixon et al., 2012; Lieberman-Aiden et al., 2009) or is restricted to only interactions mediated by a preselected protein of interest (ChIA-PET) (Handoko et al....

    [...]

  • ...(A), (B), (D), and (E) Hi-C data (adapted from Dixon et al., 2012) displayed for (A) and (D) 10 Mb and (B) and (E) 1 Mb regions around (A) and (B) Sox2 and (D) and (E)Olig1-Olig2 for mouse E14 ES cells (top) and mouse cortex (bottom)....

    [...]

  • ...in (Dixon et al., 2012) and (H) subdomain boundaries called in the present work...

    [...]

  • ...At the subcompartment level, chromatin is further organized into megabasesized topologically associating domains (TADs) that represent spatial neighborhoods of high-frequency chromatin interactions (Dixon et al., 2012; Hou et al., 2012; Nora et al., 2012; Sexton et al., 2012)....

    [...]

Journal ArticleDOI
TL;DR: Several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data are described.
Abstract: How DNA is organized in three dimensions inside the cell nucleus and how that affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic, and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C) the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction datasets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyze chromatin interaction data.

1,034 citations

Journal ArticleDOI
TL;DR: Genomes assembled de novo from short reads are highly fragmented relative to the finished chromosomes of Homo sapiens and key model organisms generated by the Human Genome Project, so genome-wide chromatin interaction data sets, such as those generated by Hi-C, are a rich source of long-range information for assigning, ordering and orienting genomic sequences to chromosomes, including across centromeres.
Abstract: Genomes assembled de novo from short reads are highly fragmented relative to the finished chromosomes of Homo sapiens and key model organisms generated by the Human Genome Project. To address this problem, we need scalable, cost-effective methods to obtain assemblies with chromosome-scale contiguity. Here we show that genome-wide chromatin interaction data sets, such as those generated by Hi-C, are a rich source of long-range information for assigning, ordering and orienting genomic sequences to chromosomes, including across centromeres. To exploit this finding, we developed an algorithm that uses Hi-C data for ultra-long-range scaffolding of de novo genome assemblies. We demonstrate the approach by combining shotgun fragment and short jump mate-pair sequences with Hi-C data to generate chromosome-scale de novo assemblies of the human, mouse and Drosophila genomes, achieving--for the human genome--98% accuracy in assigning scaffolds to chromosome groups and 99% accuracy in ordering and orienting scaffolds within chromosome groups. Hi-C data can also be used to validate chromosomal translocations in cancer genomes.

1,032 citations

References
More filters
Journal ArticleDOI
TL;DR: Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches and can be used simultaneously to achieve even greater alignment speeds.
Abstract: Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.

20,335 citations

Journal ArticleDOI
TL;DR: This work presents Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer, and uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions.
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

13,008 citations

Journal ArticleDOI
TL;DR: A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu.
Abstract: As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.

9,605 citations

Journal ArticleDOI
09 Oct 2009-Science
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.

7,180 citations

Journal ArticleDOI
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

4,166 citations


"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....

    [...]

  • ...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....

    [...]

  • ...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....

    [...]

Related Papers (5)