Spatial partitioning of the regulatory landscape of the X-inactivation centre
High-order chromatin folding in topologically associating domains has a critical role in proper long-range transcriptional control around the Xist locus, and presumably throughout the genome. Genome organization revealed The spatial organization of the genome is linked to biological function, and ad...
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Veröffentlicht in: | Nature (London) 2012-05, Vol.485 (7398), p.381-385 |
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Zusammenfassung: | High-order chromatin folding in topologically associating domains has a critical role in proper long-range transcriptional control around the
Xist
locus, and presumably throughout the genome.
Genome organization revealed
The spatial organization of the genome is linked to biological function, and advances in genomic technologies are allowing the conformation of chromosomes to be assessed genome wide. Two groups present complementary papers on the subject. Bing Ren and colleagues use Hi-C, an adaption of the chromosome conformation capture (3C) technique, to investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types. Large, megabase-sized chromatin interaction domains, termed topological domains, are found to be a pervasive and conserved feature of genome organization. Edith Heard and colleagues use chromosome conformation capture carbon-copy (5C) technology and high-resolution microscopy to obtain a high-resolution map of the chromosomal interactions over a large region of the mouse X chromosome, including the X-inactivation centre. A series of discrete topologically associating domains is revealed, as is a previously unknown long intergenic RNA with a potential regulatory role.
In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment
1
. 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)
2
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 opposite |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature11049 |