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    Spatial partitioning of the regulatory landscape of the X-inactivation centre

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    Authors
    Nora, Elphege P.
    Lajoie, Bryan R.
    Schulz, Edda G.
    Giorgetti, Luca
    Okamoto, Ikuhiro
    Servant, Nicolas
    Piolot, Tristan
    van Berkum, Nynke L.
    Meisig, Johannes
    Sedat, John
    Gribnau, Joost
    Barillot, Emmanuel
    Bluthgen, Nils
    Dekker, Job
    Heard, Edith
    Show allShow less
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Program in Systems Biology
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2012-05-17
    Keywords
    Animals
    Cell Differentiation
    DNA, Intergenic
    Embryonic Stem Cells
    Epigenesis, Genetic
    Epigenomics
    Female
    Fibroblasts
    Gene Expression Regulation
    Histones
    In Situ Hybridization, Fluorescence
    Male
    Methylation
    Mice
    Molecular Sequence Data
    Promoter Regions, Genetic
    RNA, Untranslated
    Transcriptome
    X Chromosome
    X Chromosome Inactivation
    Cell and Developmental Biology
    Genetics and Genomics
    Systems Biology
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    Link to Full Text
    http://dx.doi.org/10.1038/nature11049
    Abstract
    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.
    Source
    Nature. 2012 Apr 11;485(7398):381-5. doi: 10.1038/nature11049. Link to article on publisher's site
    DOI
    10.1038/nature11049
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49901
    PubMed ID
    22495304
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1038/nature11049
    Scopus Count
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