Long-range cis effects of ectopic X-inactivation centres on a mouse autosome.
In mammals, the X chromosome is unique in being capable of complete inactivation. Such X inactivation evolved to compensate for gene dosage differences between females with two X chromosomes and males with one. Transcriptional silencing of a single female X chromosome is controlled in cis by Xist, whose RNA product coats the inactive X chromosome (Xi), and the X-inactivation centre (Xic). A transgenic study limited the Xic to 450 kilobases including Xist, and demonstrated that it is sufficient to initiate X inactivation. Here we report that ectopic Xist RNA completely coats transgenic chromosome 12. Expression of genes over 50 centimorgans was reduced two-fold and was detected only from the normal homologue in fibroblasts. Moreover, ectopic Xic action resulted in chromosome-wide changes that are characteristic of the X(i): DNA replication was delayed, and histone H4 was markedly hypoacetylated. Our findings suggest long-range cis effects on the autosome similar to those of X inactivation, and imply that the Xic can both initiate X inactivation and drive heterochromatin formation. Thus, the potential for chromosome-wide gene regulation is not intrinsic to X-chromosome DNA, but can also occur on autosomes possessing the Xic.
Lee
J T
JT
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. jlee@wi.mit.edu
Jaenisch
R
R
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics; D004303:Dosage Compensation, Genetic; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression; D016762:Genes, fos; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D006570:Heterochromatin; D006657:Histones; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C077885:XIST non-coding RNA; D012313:RNA