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dc.contributor.authorNora, Elphege P.
dc.contributor.authorLajoie, Bryan R.
dc.contributor.authorSchulz, Edda G.
dc.contributor.authorGiorgetti, Luca
dc.contributor.authorOkamoto, Ikuhiro
dc.contributor.authorServant, Nicolas
dc.contributor.authorPiolot, Tristan
dc.contributor.authorvan Berkum, Nynke L.
dc.contributor.authorMeisig, Johannes
dc.contributor.authorSedat, John
dc.contributor.authorGribnau, Joost
dc.contributor.authorBarillot, Emmanuel
dc.contributor.authorBluthgen, Nils
dc.contributor.authorDekker, Job
dc.contributor.authorHeard, Edith
dc.date2022-08-11T08:10:59.000
dc.date.accessioned2022-08-23T17:27:36Z
dc.date.available2022-08-23T17:27:36Z
dc.date.issued2012-05-17
dc.date.submitted2012-08-10
dc.identifier.citationNature. 2012 Apr 11;485(7398):381-5. doi: 10.1038/nature11049. <a href="http://dx.doi.org/10.1038/nature11049">Link to article on publisher's site</a>
dc.identifier.issn0028-0836 (Linking)
dc.identifier.doi10.1038/nature11049
dc.identifier.pmid22495304
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49901
dc.description.abstractIn eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. 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) 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22495304&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1038/nature11049
dc.subjectAnimals
dc.subjectCell Differentiation
dc.subjectDNA, Intergenic
dc.subjectEmbryonic Stem Cells
dc.subjectEpigenesis, Genetic
dc.subjectEpigenomics
dc.subjectFemale
dc.subjectFibroblasts
dc.subjectGene Expression Regulation
dc.subjectHistones
dc.subjectIn Situ Hybridization, Fluorescence
dc.subjectMale
dc.subjectMethylation
dc.subjectMice
dc.subjectMolecular Sequence Data
dc.subjectPromoter Regions, Genetic
dc.subjectRNA, Untranslated
dc.subjectTranscriptome
dc.subjectX Chromosome
dc.subjectX Chromosome Inactivation
dc.subjectCell and Developmental Biology
dc.subjectGenetics and Genomics
dc.subjectSystems Biology
dc.titleSpatial partitioning of the regulatory landscape of the X-inactivation centre
dc.typeJournal Article
dc.source.journaltitleNature
dc.source.volume485
dc.source.issue7398
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/sysbio_pubs/2
dc.identifier.contextkey3201818
html.description.abstract<p>In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. 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) 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.</p>
dc.identifier.submissionpathsysbio_pubs/2
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Systems Biology
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pages381-5


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