Spatial partitioning of the regulatory landscape of the X-inactivation centre
Elphège P. Nora,Bryan R. Lajoie,Edda G. Schulz,Luca Giorgetti,Luca Giorgetti,Luca Giorgetti,Ikuhiro Okamoto,Ikuhiro Okamoto,Ikuhiro Okamoto,Nicolas Servant,Nicolas Servant,Nicolas Servant,Tristan Piolot,Tristan Piolot,Tristan Piolot,Nynke L. van Berkum,Johannes Meisig,John W. Sedat,Joost Gribnau,Emmanuel Barillot,Emmanuel Barillot,Emmanuel Barillot,Nils Blüthgen,Job Dekker,Edith Heard,Edith Heard,Edith Heard +26 more
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TLDR
In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, this study sets the stage for the full genetic dissection of the mouse X-inactivation centre.Abstract:
High-order chromatin folding in topologically associating domains has a critical role in proper long-range transcriptional control around the Xist locus, and presumably throughout the genome. The spatial organization of the genome is linked to biological function, and advances in genomic technologies are allowing the conformation of chromosomes to be assessed genome wide. Two groups present complementary papers on the subject. Bing Ren and colleagues use Hi-C, an adaption of the chromosome conformation capture (3C) technique, to investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types. Large, megabase-sized chromatin interaction domains, termed topological domains, are found to be a pervasive and conserved feature of genome organization. Edith Heard and colleagues use chromosome conformation capture carbon-copy (5C) technology and high-resolution microscopy to obtain a high-resolution map of the chromosomal interactions over a large region of the mouse X chromosome, including the X-inactivation centre. A series of discrete topologically associating domains is revealed, as is a previously unknown long intergenic RNA with a potential regulatory role. In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment1. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C)2 and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.read more
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A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Suhas S.P. Rao,Miriam H. Huntley,Neva C. Durand,Elena K. Stamenova,Ivan D. Bochkov,James T. Robinson,James T. Robinson,Adrian L. Sanborn,Ido Machol,Ido Machol,Arina D. Omer,Arina D. Omer,Eric S. Lander,Eric S. Lander,Eric S. Lander,Erez Lieberman Aiden +15 more
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.
Journal ArticleDOI
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Jesse R. Dixon,Siddarth Selvaraj,Siddarth Selvaraj,Feng Yue,Audrey Kim,Yan-Yan Li,Yin-Zhong Shen,Ming Hu,Jun Liu,Bing Ren,Bing Ren +10 more
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.
Journal ArticleDOI
Long Noncoding RNAs: Cellular Address Codes in Development and Disease
Pedro J. Batista,Howard Y. Chang +1 more
TL;DR: Long noncoding RNAs (lncRNAs) have emerged as key components of the address code, allowing protein complexes, genes, and chromosomes to be trafficked to appropriate locations and subject to proper activation and deactivation.
Journal ArticleDOI
Transcription factors: from enhancer binding to developmental control.
TL;DR: Current knowledge of transcription factor function from genomic and genetic studies is reviewed and how different strategies, including extensive cooperative regulation, progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development are discussed.
Journal ArticleDOI
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
Darío G. Lupiáñez,Darío G. Lupiáñez,Katerina Kraft,Katerina Kraft,Verena Heinrich,Peter Krawitz,Peter Krawitz,Francesco Brancati,Eva Klopocki,Denise Horn,Hülya Kayserili,John M. Opitz,Renata Laxova,Fernando Santos-Simarro,Fernando Santos-Simarro,Brigitte Gilbert-Dussardier,Lars Wittler,Marina Borschiwer,Stefan A. Haas,Marco Osterwalder,Martin Franke,Martin Franke,Bernd Timmermann,Jochen Hecht,Jochen Hecht,Malte Spielmann,Malte Spielmann,Axel Visel,Axel Visel,Axel Visel,Stefan Mundlos,Stefan Mundlos +31 more
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.
References
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Journal ArticleDOI
Comprehensive mapping of long-range interactions reveals folding principles of the human genome.
Erez Lieberman Aiden,Nynke L. van Berkum,Louise Williams,Maxim Imakaev,Tobias Ragoczy,Tobias Ragoczy,Agnes Telling,Agnes Telling,Ido Amit,Bryan R. Lajoie,Peter J. Sabo,Michael O. Dorschner,Richard Sandstrom,Bradley E. Bernstein,Bradley E. Bernstein,Michaël Bender,Mark Groudine,Mark Groudine,Andreas Gnirke,John A. Stamatoyannopoulos,Leonid A. Mirny,Eric S. Lander,Eric S. Lander,Job Dekker +23 more
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.
Journal ArticleDOI
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Jesse R. Dixon,Siddarth Selvaraj,Siddarth Selvaraj,Feng Yue,Audrey Kim,Yan-Yan Li,Yin-Zhong Shen,Ming Hu,Jun Liu,Bing Ren,Bing Ren +10 more
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.
Journal ArticleDOI
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Mitchell Guttman,Ido Amit,Manuel Garber,Courtney French,Michael F. Lin,David M. Feldser,Maite Huarte,Maite Huarte,Or Zuk,Bryce W. Carey,John P. Cassady,Moran N. Cabili,Rudolf Jaenisch,Tarjei S. Mikkelsen,Tyler Jacks,Nir Hacohen,Bradley E. Bernstein,Bradley E. Bernstein,Manolis Kellis,Manolis Kellis,Aviv Regev,John L. Rinn,John L. Rinn,John L. Rinn,Eric S. Lander +24 more
TL;DR: It is demonstrated that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFκB, Sox2, Oct4 (also known as Pou5f1) and Nanog, defining a unique collection of functional linc RNAs that are highly conserved and implicated in diverse biological processes.
Journal ArticleDOI
Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
Ahmad M. Khalil,Mitchell Guttman,Maite Huarte,Manuel Garber,Arjun Raj,Dianali Rivea Morales,Kelly Thomas,Aviva Presser,Bradley E. Bernstein,Alexander van Oudenaarden,Aviv Regev,Eric S. Lander,John L. Rinn +12 more
TL;DR: A model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression is proposed, and it is shown that siRNA-mediated depletion of certain linc RNAs associated with PRC2 leads to changes in gene expression.
Journal ArticleDOI
Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome
Tom Sexton,Eitan Yaffe,Ephraim Kenigsberg,Frédéric Bantignies,Benjamin Leblanc,Michael Hoichman,Hugues Parrinello,Amos Tanay,Giacomo Cavalli +8 more
TL;DR: A high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei is presented, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.
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