Human X inactivation center induces random X chromosome inactivation in male transgenic mice.
X chromosome inactivation is the means to downregulate the transcriptional output of X chromosomes in female mammals. Essential DNA from the murine X inactivation center (Xic) has been identified by introducing it into male embryonic stem (ES) cells. To identify the essential sequences on human X chromosomes, we transfected male mouse ES cells with a YAC transgene containing 480 kb of the putative human X inactivation center (XIC). Despite little DNA sequence conservation, the human transgene is recognized as a second Xic in these XY mouse cells and induces random inactivation in chimeric mice derived from these cells. Inactivation is extensive on the X chromosome, but more localized on chromosome 11 carrying the transgene, demonstrating that initial inactivation and spreading of inactivation signals along the chromosome are independent events. Our results show for the first time that the DNA included in the human XIC transgene is sufficient to initiate random X inactivation, even in cells of another species. Interspecies XIC trangenes should facilitate further investigation of this process in humans and other mammals.
McKusick Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287-3914, USA. bmigeon@welchlink.welch.jhu.edu
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Migeon
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Kazi
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Haisley-Royster
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Hu
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Reeves
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Call
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Lawler
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Moore
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Morrison
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Jeppesen
D000818:Animals; D002678:Chimera; D004303:Dosage Compensation, Genetic; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*
D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C077885:XIST non-coding RNA