title: Skewing X chromosome choice by modulating sense transcription across the Xist locus.
abstract: The X-inactive-specific transcript (Xist) locus is a cis-acting switch that regulates X chromosome inactivation in mammals. Over recent years an important goal has been to understand how Xist is regulated at the initiation of X inactivation. Here we report the analysis of a series of targeted mutations at the 5' end of the Xist locus. A number of these mutations were found to cause preferential inactivation, to varying degrees, of the X chromosome bearing the targeted allele in XX heterozygotes. This phenotype is similar to that seen with mutations that ablate Tsix, an antisense RNA initiated 3' of Xist. Interestingly, each of the 5' mutations causing nonrandom X inactivation was found to exhibit ectopic sense transcription in embryonic stem (ES) cells. The level of ectopic transcription was seen to correlate with the degree of X inactivation skewing. Conversely, targeted mutations which did not affect randomness of X inactivation also did not exhibit ectopic sense transcription. These results indicate that X chromosome choice is determined by the balance of Xist sense and antisense transcription prior to the onset of random X inactivation.
authors.affiliation: X Inactivation Group, MRC Clinical Sciences Centre, Faculty of Medicine ICSTM, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Tatyana B
authors.initials: TB
authors.lastname: Nesterova
authors.forename: Colette M
authors.initials: CM
authors.lastname: Johnston
authors.forename: Ruth
authors.initials: R
authors.lastname: Appanah
authors.forename: Alistair E T
authors.initials: AE
authors.lastname: Newall
authors.forename: Jonathan
authors.initials: J
authors.lastname: Godwin
authors.forename: Maria
authors.initials: M
authors.lastname: Alexiou
authors.forename: Neil
authors.initials: N
authors.lastname: Brockdorff
mesh_terms: D000818:Animals; D004303:Dosage Compensation, Genetic; D005786:Gene Expression Regulation / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C472177:Enox protein, mouse; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA