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

Nora, E. P., Lajoie, B. R., Schulz, E. G., Giorgetti, L., Okamoto, I., Servant, N., et al. (2012). Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature, 485(7398), 381-385. doi:10.1038/nature11049.

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Nora, Elphège P., Author
Lajoie, Bryan R., Author
Schulz, Edda G.1, Author           
Giorgetti, Luca, Author
Okamoto, Ikuhiro, Author
Servant, Nicolas, Author
Piolot, Tristan, Author
van Berkum, Nynke L., Author
Meisig, Johannes, Author
Sedat, John, Author
Gribnau, Joost, Author
Barillot, Emmanuel, Author
Blüthgen, Nils, Author
Dekker, Job, Author
Heard, Edith, Author
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1Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117286              

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 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.

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Language(s): eng - English
 Dates: 2012-04-112012-05-17
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nature11049
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 485 (7398) Sequence Number: - Start / End Page: 381 - 385 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238