Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

doi:10.1016/J.CELL.2015.04.004

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Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Journal Article•DOI•

Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Darío G. Lupiáñez¹, Darío G. Lupiáñez², Katerina Kraft¹, Katerina Kraft², Verena Heinrich², Peter Krawitz², Peter Krawitz¹, Francesco Brancati³, Eva Klopocki⁴, Denise Horn², Hülya Kayserili⁵, John M. Opitz⁶, Renata Laxova⁶, Fernando Santos-Simarro⁷, Fernando Santos-Simarro⁸, Brigitte Gilbert-Dussardier, Lars Wittler¹, Marina Borschiwer¹, Stefan A. Haas¹, Marco Osterwalder⁹, Martin Franke¹, Martin Franke², Bernd Timmermann¹, Jochen Hecht¹, Jochen Hecht², Malte Spielmann², Malte Spielmann¹, Axel Visel⁹, Axel Visel¹⁰, Axel Visel¹¹, Stefan Mundlos¹, Stefan Mundlos² - Show less +28 more•Institutions (11)

Max Planck Society¹, Charité², University of Rome Tor Vergata³, University of Würzburg⁴, Istanbul University⁵, University of Utah⁶, Hospital Universitario La Paz⁷, Carlos III Health Institute⁸, Lawrence Berkeley National Laboratory⁹, University of California, Merced¹⁰, United States Department of Energy¹¹

21 May 2015-Cell (Cell Press)-Vol. 161, Iss: 5, pp 1012-1025

TL;DR: The results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

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About: This article is published in Cell.The article was published on 2015-05-21 and is currently open access. It has received 1677 citations till now. The article focuses on the topics: Chromosome conformation capture & Enhancer.

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Journal Article•DOI•

Formation of Chromosomal Domains by Loop Extrusion

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Geoffrey Fudenberg¹, Maxim Imakaev¹, Carolyn Lu¹, Anton Goloborodko¹, Nezar Abdennur¹, Leonid A. Mirny¹, Leonid A. Mirny² - Show less +3 more•Institutions (2)

Massachusetts Institute of Technology¹, Harvard University²

31 May 2016-Cell Reports

TL;DR: This model produces TADs and finer-scale features of Hi-C data because each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops.

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1,479 citations

Cites background from "Disruptions of Topological Chromati..."

...2038 Cell Reports 15, 2038–2049, May 31, 2016 a 2016 The Author(s This is an open access article under the CC BY-NC-ND license (http:// ment (Andrey et al., 2013; Lupiáñez et al., 2015; Symmons et al., 2014)....
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...…found important functional roles for TADs in the control of gene expression and develop- 2038 Cell Reports 15, 2038–2049, May 31, 2016 ª 2016 The Author(s This is an open access article under the CC BY-NC-ND license (http:// ment (Andrey et al., 2013; Lupiáñez et al., 2015; Symmons et al., 2014)....
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Journal Article•DOI•

Cohesin Loss Eliminates All Loop Domains

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Suhas S.P. Rao¹, Suhas S.P. Rao², Su Chen Huang², Brian Glenn St Hilaire³, Brian Glenn St Hilaire², Jesse M. Engreitz⁴, Elizabeth M. Perez⁴, Kyong-Rim Kieffer-Kwon, Adrian L. Sanborn², Adrian L. Sanborn³, Adrian L. Sanborn¹, Sarah E. Johnstone⁴, Sarah E. Johnstone⁵, Gavin D. Bascom⁶, Ivan D. Bochkov², Xingfan Huang², Xingfan Huang³, Muhammad S. Shamim², Muhammad S. Shamim³, Jaeweon Shin², Jaeweon Shin³, Douglass Turner², Douglass Turner⁷, Ziyi Ye², Ziyi Ye³, Arina D. Omer², James T. Robinson⁴, James T. Robinson⁷, James T. Robinson², Tamar Schlick⁸, Tamar Schlick⁶, Tamar Schlick⁹, Bradley E. Bernstein⁵, Bradley E. Bernstein⁴, Rafael Casellas¹⁰, Eric S. Lander¹¹, Eric S. Lander⁴, Eric S. Lander⁵, Erez Lieberman Aiden - Show less +35 more•Institutions (11)

Stanford University¹, Baylor College of Medicine², Rice University³, Broad Institute⁴, Harvard University⁵, New York University⁶, University of California, San Diego⁷, New York University Shanghai⁸, Courant Institute of Mathematical Sciences⁹, National Institutes of Health¹⁰, Massachusetts Institute of Technology¹¹

05 Oct 2017-Cell

TL;DR: In this paper, the effects of degrading cohesin were explored, showing that loop domains can be eliminated and re-formed in under an hour, consistent with a model where loop extrusion is rapid.

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1,290 citations

Journal Article•DOI•

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.

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Elphège P. Nora, Anton Goloborodko¹, Anne-Laure Valton², Johan H. Gibcus², Alec Uebersohn, Nezar Abdennur¹, Job Dekker², Leonid A. Mirny¹, Benoit G. Bruneau - Show less +5 more•Institutions (2)

Massachusetts Institute of Technology¹, University of Massachusetts Medical School²

18 May 2017-Cell

TL;DR: The data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading, and provides new fundamental insights into the rules governing mammalian genome organization.

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1,259 citations

Cites background or result from "Disruptions of Topological Chromati..."

...Deleting such a TAD boundary, or even just the underlying CTCF site, can lead to loss of physical insulation and subsequent encapsulation of the two abutting TADs into a single domain (Lupiáñez et al., 2015; Narendra et al., 2015; Nora et al., 2012; Sanborn et al., 2015; Tsujimura et al., 2015)....
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...This observation supports, at the genome-wide level, the notion that CTCF can mediate enhancer-blocking insulation through the specification of TAD boundaries, in line with previous locus-specific studies (Dowen et al., 2014; Doyle et al., 2014; Lupiáñez et al., 2015; Nora et al., 2012)....
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...This arrangement is important: inverting a single CTCF site can be enough to rewire the direction of looping and disrupt proper packaging of the underlying chromosomal segment into an insulated TAD (Guo et al., 2015; Lupiáñez et al., 2015; Sanborn et al., 2015; de Wit et al., 2015)....
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...This arrangement is important: inverting a single CTCF site can be enough to rewire the direction of looping and disrupt proper packaging of the underlying chromosomal segment into an insulated TAD (Guo et al., 2015; Lupiáñez et al., 2015; Sanborn et al., 2015; de Wit et al., 2015)....
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...This observation supports, at the genome-wide level, the notion that CTCF can mediate enhancer-blocking insulation through the specification of TAD boundaries, in line with previous locus-specific studies (Dowen et al., 2014; Doyle et al., 2014; Lupiáñez et al., 2015; Nora et al., 2012)....
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Journal Article•DOI•

Insulator dysfunction and oncogene activation in IDH mutant gliomas

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William A. Flavahan¹, Yotam Drier², Yotam Drier³, Yotam Drier¹, Brian B. Liau³, Brian B. Liau¹, Brian B. Liau², Shawn M. Gillespie², Shawn M. Gillespie³, Shawn M. Gillespie¹, Andrew S. Venteicher¹, Andrew S. Venteicher³, Anat Stemmer-Rachamimov¹, Mario L. Suvà¹, Mario L. Suvà³, Bradley E. Bernstein¹, Bradley E. Bernstein³, Bradley E. Bernstein² - Show less +14 more•Institutions (3)

Harvard University¹, Howard Hughes Medical Institute², Broad Institute³

07 Jan 2016-Nature

TL;DR: Human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein, and manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear.

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Abstract: Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.

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1,005 citations

Journal Article•DOI•

Multiscale 3D Genome Rewiring during Mouse Neural Development

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Boyan B. Bonev¹, Netta Mendelson Cohen², Quentin Szabo¹, Lauriane Fritsch¹, Giorgio L. Papadopoulos¹, Yaniv Lubling², Xiaole Xu, Xiaodan Lv, Jean-Philippe Hugnot¹, Amos Tanay², Giacomo Cavalli¹ - Show less +7 more•Institutions (2)

University of Montpellier¹, Weizmann Institute of Science²

19 Oct 2017-Cell

TL;DR: This work comprehensively mapped 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest-resolution Hi-C maps available to date and shows that multiple factors influence the dynamics of chromatin interactions in development.

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973 citations

Cites background from "Disruptions of Topological Chromati..."

...Domain insulation has been shown to be important for gene expression and physiology (Flavahan et al., 2016; Lupiáñez et al., 2015)....
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...Domain insulation has been shown to be important for gene expression and physiology (Flavahan et al., 2016; Lupiáñez et al., 2015)....
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References

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Journal Article•DOI•

STAR: ultrafast universal RNA-seq aligner

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Alexander Dobin¹, Carrie A. Davis¹, Felix Schlesinger¹, Jorg Drenkow¹, Chris Zaleski¹, Sonali Jha¹, Philippe Batut¹, Mark Chaisson¹, Thomas R. Gingeras¹ - Show less +5 more•Institutions (1)

Cold Spring Harbor Laboratory¹

01 Jan 2013-Bioinformatics

TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.

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Abstract: Motivation Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. Results To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. Availability and implementation STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.

...read moreread less

30,684 citations

Journal Article•DOI•

Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks

[...]

Cole Trapnell¹, Adam Roberts², Loyal A. Goff³, Loyal A. Goff¹, Loyal A. Goff⁴, Geo Pertea⁵, Daehwan Kim⁶, Daehwan Kim⁷, David R. Kelley⁴, David R. Kelley¹, Harold Pimentel², Steven L. Salzberg⁵, John L. Rinn¹, John L. Rinn⁴, Lior Pachter² - Show less +11 more•Institutions (7)

Broad Institute¹, University of California, Berkeley², Massachusetts Institute of Technology³, Harvard University⁴, Johns Hopkins University⁵, Johns Hopkins University School of Medicine⁶, University of Maryland, College Park⁷

01 Mar 2012-Nature Protocols

TL;DR: This protocol begins with raw sequencing reads and produces a transcriptome assembly, lists of differentially expressed and regulated genes and transcripts, and publication-quality visualizations of analysis results, which takes less than 1 d of computer time for typical experiments and ∼1 h of hands-on time.

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Abstract: Recent advances in high-throughput cDNA sequencing (RNA-seq) can reveal new genes and splice variants and quantify expression genome-wide in a single assay. The volume and complexity of data from RNA-seq experiments necessitate scalable, fast and mathematically principled analysis software. TopHat and Cufflinks are free, open-source software tools for gene discovery and comprehensive expression analysis of high-throughput mRNA sequencing (RNA-seq) data. Together, they allow biologists to identify new genes and new splice variants of known ones, as well as compare gene and transcript expression under two or more conditions. This protocol describes in detail how to use TopHat and Cufflinks to perform such analyses. It also covers several accessory tools and utilities that aid in managing data, including CummeRbund, a tool for visualizing RNA-seq analysis results. Although the procedure assumes basic informatics skills, these tools assume little to no background with RNA-seq analysis and are meant for novices and experts alike. The protocol begins with raw sequencing reads and produces a transcriptome assembly, lists of differentially expressed and regulated genes and transcripts, and publication-quality visualizations of analysis results. The protocol's execution time depends on the volume of transcriptome sequencing data and available computing resources but takes less than 1 d of computer time for typical experiments and ∼1 h of hands-on time.

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10,913 citations

Journal Article•DOI•

Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

[...]

Erez Lieberman Aiden¹, Nynke L. van Berkum², Louise Williams¹, Maxim Imakaev¹, Tobias Ragoczy³, Tobias Ragoczy⁴, Agnes Telling³, Agnes Telling⁴, Ido Amit¹, Bryan R. Lajoie², Peter J. Sabo³, Michael O. Dorschner³, Richard Sandstrom³, Bradley E. Bernstein¹, Bradley E. Bernstein⁵, Michaël Bender³, Mark Groudine³, Mark Groudine⁴, Andreas Gnirke¹, John A. Stamatoyannopoulos³, Leonid A. Mirny¹, Eric S. Lander⁵, Eric S. Lander¹, Job Dekker² - Show less +20 more•Institutions (5)

Massachusetts Institute of Technology¹, University of Massachusetts Medical School², University of Washington³, Fred Hutchinson Cancer Research Center⁴, Harvard University⁵

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.

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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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7,180 citations

"Disruptions of Topological Chromati..." refers background in this paper

...In parallel, sequencing-based studies of DNA-DNA interactions have provided insight into the general conformation of the genome in living cells, as well as interactions between promoters and distant-acting transcriptional enhancers in specific cell types (Lieberman-Aiden et al., 2009)....
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Journal Article•DOI•

A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping

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Suhas S.P. Rao¹, Miriam H. Huntley¹, Neva C. Durand, Elena K. Stamenova, Ivan D. Bochkov¹, James T. Robinson¹, James T. Robinson², Adrian L. Sanborn¹, Ido Machol³, Ido Machol¹, Arina D. Omer³, Arina D. Omer¹, Eric S. Lander⁴, Eric S. Lander⁵, Eric S. Lander², Erez Lieberman Aiden - Show less +12 more•Institutions (5)

Baylor College of Medicine¹, Broad Institute², Rice University³, Harvard University⁴, Massachusetts Institute of Technology⁵

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.

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5,945 citations

"Disruptions of Topological Chromati..." refers background in this paper

...While the present study focused on one locus and one set of related morphological phenotypes, TAD data for the entire human and mouse genome are becoming available at increasing resolution (Jin et al., 2013; Rao et al., 2014)....
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Journal Article•DOI•

Topological domains in mammalian genomes identified by analysis of chromatin interactions

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Jesse R. Dixon¹, Siddarth Selvaraj¹, Siddarth Selvaraj², Feng Yue¹, Audrey Kim¹, Yan-Yan Li¹, Yin-Zhong Shen¹, Ming Hu³, Jun Liu³, Bing Ren², Bing Ren¹ - Show less +7 more•Institutions (3)

Ludwig Institute for Cancer Research¹, University of California, San Diego², Harvard University³

17 May 2012-Nature

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.

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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.

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5,774 citations

"Disruptions of Topological Chromati..." refers background or methods in this paper

...TADs are stable units of genomic architecture that have been proposed to partition the genome into large regulatory units (Dixon et al., 2012)....
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...Hi-C data show that the region is organized into three adjacent TADs, the largest encompassing EPHA4 (Figure 1A) (Dixon et al., 2012)....
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...…approaches such as Hi-C (a high-throughput variant of the chromosome conformation capture technique [3C]) and 5C (chromosome conformation capture carbon copy) show that the genome is partitioned into megabase-scale topologically associated domains (TADs) (Dixon et al., 2012; Nora et al., 2012)....
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...They are separated by boundary regions that often contain CTCF binding sites or housekeeping genes representing de facto insulators that block interactions across adjacent TADs (Dixon et al., 2012)....
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...Previous studies showed that TADs are highly stable across species and cell lines (Dixon et al., 2012), raising the possibility that patient-derived samples can provide direct insight into regulatory aberrations that affect early embryonic development....
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