Publication Date:
2013-10-29
Description:
The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes. During XCI, Xist coats the future inactive X chromosome (Xi) and recruits Polycomb repressive complex 2 (PRC2) to the X-inactivation centre (Xic). How Xist spreads silencing on a 150-megabases scale is unclear. Here we generate high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), indicating co-migration of Xist and PRC2. Interestingly, when Xist is acutely stripped off from the Xi in post-XCI cells, Xist recovers quickly within both gene-rich and gene-poor domains on a timescale of hours instead of days, indicating a previously primed Xi chromatin state. We conclude that Xist spreading takes distinct stage-specific forms. During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and gene-poor regions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904790/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904790/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simon, Matthew D -- Pinter, Stefan F -- Fang, Rui -- Sarma, Kavitha -- Rutenberg-Schoenberg, Michael -- Bowman, Sarah K -- Kesner, Barry A -- Maier, Verena K -- Kingston, Robert E -- Lee, Jeannie T -- F32-GM090765/GM/NIGMS NIH HHS/ -- R01 GM043901/GM/NIGMS NIH HHS/ -- R01 GM090278/GM/NIGMS NIH HHS/ -- R01-GM043901/GM/NIGMS NIH HHS/ -- R01-GM090278/GM/NIGMS NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):465-9. doi: 10.1038/nature12719. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Molecular Biophysics and Biochemistry, and Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA [3]. ; 1] Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3]. ; 1] Department of Molecular Biophysics and Biochemistry, and Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA [2]. ; 1] Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Molecular Biophysics and Biochemistry, and Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA. ; Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162848" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Chromatin/genetics/metabolism
;
Embryonic Stem Cells/metabolism
;
Female
;
Fibroblasts/metabolism
;
Gene Silencing
;
Genes
;
Histone-Lysine N-Methyltransferase/metabolism
;
Histones/chemistry/metabolism
;
Lysine/metabolism
;
Methylation
;
Mice
;
Models, Genetic
;
RNA, Long Noncoding/genetics/*metabolism
;
X Chromosome/genetics/*metabolism
;
*X Chromosome Inactivation/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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