Publication Date:
2010-11-19
Description:
The reprogramming of X-chromosome inactivation during the acquisition of pluripotency in vivo and in vitro is accompanied by the repression of Xist, the trigger of X-inactivation, and the upregulation of its antisense counterpart Tsix. We have shown that key factors supporting pluripotency-Nanog, Oct4 and Sox2-bind within Xist intron 1 in undifferentiated embryonic stem cells (ESC) to repress Xist transcription. However, the relationship between transcription factors of the pluripotency network and Tsix regulation has remained unclear. Here we show that Tsix upregulation in embryonic stem cells depends on the recruitment of the pluripotent marker Rex1, and of the reprogramming-associated factors Klf4 and c-Myc, by the DXPas34 minisatellite associated with the Tsix promoter. Upon deletion of DXPas34, binding of the three factors is abrogated and the transcriptional machinery is no longer efficiently recruited to the Tsix promoter. Additional analyses including knockdown experiments further demonstrate that Rex1 is critically important for efficient transcription elongation of Tsix. Hence, distinct embryonic-stem-cell-specific complexes couple X-inactivation reprogramming and pluripotency, with Nanog, Oct4 and Sox2 repressing Xist to facilitate the reactivation of the inactive X, and Klf4, c-Myc and Rex1 activating Tsix to remodel Xist chromatin and ensure random X-inactivation upon differentiation. The holistic pattern of Xist/Tsix regulation by pluripotent factors that we have identified suggests a general direct governance of complex epigenetic processes by the machinery dedicated to pluripotency.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Navarro, Pablo -- Oldfield, Andrew -- Legoupi, Julie -- Festuccia, Nicola -- Dubois, Agnes -- Attia, Mikael -- Schoorlemmer, Jon -- Rougeulle, Claire -- Chambers, Ian -- Avner, Philip -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Nov 18;468(7322):457-60. doi: 10.1038/nature09496.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France. pablo.navarro@ed.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21085182" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Embryonic Stem Cells/cytology/*metabolism
;
Female
;
Homeodomain Proteins/metabolism
;
Kruppel-Like Transcription Factors/metabolism
;
Male
;
Mice
;
Minisatellite Repeats/genetics
;
Octamer Transcription Factor-3/metabolism
;
Pluripotent Stem Cells/cytology/*metabolism
;
Promoter Regions, Genetic/genetics
;
Proto-Oncogene Proteins c-myc/metabolism
;
RNA, Long Noncoding
;
RNA, Untranslated/*genetics
;
SOXB1 Transcription Factors/metabolism
;
Transcription Factors/metabolism
;
Transcription, Genetic/*genetics
;
Up-Regulation/*genetics
;
X Chromosome Inactivation/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
