Primary non-random X inactivation associated with disruption of Xist promoter regulation.
In this report we demonstrate primary non-random X chromosome inactivation following targeted mutagenesis of a region immediately upstream of XIST promoter P(1). In heterozygous animals there is a preferential inactivation of the targeted X chromosome in 80--90% of cells. The phenotype correlates with inappropriate activation of XIST in a proportion of the mutant XY embryonic stem cells. Strand-specific analysis revealed increased sense transcription initiating upstream of XIST promoter P(1). There was, however, no discernible effect on transcription from the antisense Tsix gene. We demonstrate that the in vitro and in vivo phenotypes are specifically attributable to the presence of a PGKneo cassette at the targeted locus. These findings are discussed in the context of understanding mechanisms of XIST gene regulation in X inactivation.
X inactivation Group, MRC Clinical Sciences Centre, ICSM, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
A E
AE
Newall
S
S
Duthie
E
E
Formstone
T
T
Nesterova
M
M
Alexiou
C
C
Johnston
M L
ML
Caparros
N
N
Brockdorff
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D004303:Dosage Compensation, Genetic; D017353:Gene Deletion; D051379:Mice; D016296:Mutagenesis; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000037:antagonists & inhibitors / Q000235:genetics*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*
D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C077885:XIST non-coding RNA