Spatial partitioning of the regulatory landscape of the X-inactivation centre
AuthorsNora, Elphege P.
Lajoie, Bryan R.
Schulz, Edda G.
van Berkum, Nynke L.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Program in Systems Biology
Program in Gene Function and Expression
Document TypeJournal Article
Embryonic Stem Cells
Gene Expression Regulation
In Situ Hybridization, Fluorescence
Molecular Sequence Data
Promoter Regions, Genetic
X Chromosome Inactivation
Cell and Developmental Biology
Genetics and Genomics
MetadataShow full item record
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.
SourceNature. 2012 Apr 11;485(7398):381-5. doi: 10.1038/nature11049. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/49901
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