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Spatial partitioning of the regulatory landscape of the X-inactivation centre
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
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Systems Biology
Program in Gene Function and Expression
Document Type
Journal ArticlePublication Date
2012-05-17Keywords
AnimalsCell 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
Metadata
Show full item recordAbstract
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 siteDOI
10.1038/nature11049Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49901PubMed ID
22495304Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nature11049