title: The pluripotency factor-bound intron 1 of Xist is dispensable for X chromosome inactivation and reactivation in vitro and in vivo.
abstract: X chromosome inactivation (XCI) is a dynamically regulated developmental process with inactivation and reactivation accompanying the loss and gain of pluripotency, respectively. A functional relationship between pluripotency and lack of XCI has been suggested, whereby pluripotency transcription factors repress the master regulator of XCI, the noncoding transcript Xist, by binding to its first intron (intron 1). To test this model, we have generated intron 1 mutant embryonic stem cells (ESCs) and two independent mouse models. We found that Xist's repression in ESCs, its transcriptional upregulation upon differentiation, and its silencing upon reprogramming to pluripotency are not dependent on intron 1. Although we observed subtle effects of intron 1 deletion on the randomness of XCI and in the absence of the antisense transcript Tsix in differentiating ESCs, these have little relevance in vivo because mutant mice do not deviate from Mendelian ratios of allele transmission. Altogether, our findings demonstrate that intron 1 is dispensable for the developmental dynamics of Xist expression.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Alissa
authors.initials: A
authors.lastname: Minkovsky
authors.forename: Tahsin Stefan
authors.initials: TS
authors.lastname: Barakat
authors.forename: Nadia
authors.initials: N
authors.lastname: Sellami
authors.forename: Mark Henry
authors.initials: MH
authors.lastname: Chin
authors.forename: Nilhan
authors.initials: N
authors.lastname: Gunhanlar
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
authors.forename: Kathrin
authors.initials: K
authors.lastname: Plath
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007438:Introns; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D049951:X Chromosome Inactivation
chemical_list: D062085:RNA, Long Noncoding; D014157:Transcription Factors; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA