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First published online 26 November 2008
doi: 10.1242/dev.026427

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: dev.026427v1 136/1/139    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hoki, Y. Articles by Sado, T. Search for Related Content PubMed PubMed Citation Articles by Hoki, Y. Articles by Sado, T. Social Bookmarking                         What's this?

A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse

Yuko Hoki^1,*, Naomi Kimura^1,*, Minako Kanbayashi¹, Yuko Amakawa^1,2, Tatsuya Ohhata¹, Hiroyuki Sasaki^1,2 and Takashi Sado^1,2,

¹ Division of Human Genetics, National Institute of Genetics, Research Organization of Information and Systems, 1111 Yata, Mishima 411-8540, Japan.
² Department of Genetics, The Graduate University for Advanced Studies (Sokendai), 1111 Yata, Mishima 411-8540, Japan.

Author for correspondence (e-mail: tsado{at}lab.nig.ac.jp)

Accepted 29 October 2008

X-inactivation in female mammals is triggered by the association of non-coding Xist RNA in cis with the X chromosome. Although it has been suggested that the A-repeat located in the proximal part of the Xist RNA is required for chromosomal silencing in ES cells, its role in mouse has not yet been addressed. Here, we deleted the A-repeat in mouse and studied its effects on X-inactivation during embryogenesis. The deletion, when paternally transmitted, caused a failure of imprinted X-inactivation in the extraembryonic tissues, demonstrating the essential role of the A-repeat in X-inactivation in the mouse embryo. Unexpectedly, the failure of X-inactivation was caused by a lack of Xist RNA rather than by a defect in the silencing function of the mutated RNA, which we expected to be expressed from the mutated X. Interestingly, the normally silent paternal copy of Tsix, which is an antisense negative regulator of Xist, was ectopically activated in the preimplantation embryo. Furthermore, CpG sites in the promoter region of paternal Xist, which are essentially unmethylated in the extraembryonic tissues of the wild-type female embryo, acquire a significant level of methylation on the mutated paternal X. These findings demonstrate that the DNA sequence deleted on the mutated X, most probably the A-repeat, is essential as a genomic element for the appropriate transcriptional regulation of the Xist/Tsix loci and subsequent X-inactivation in the mouse embryo.

Key words: X-inactivation, Xist, Tsix, Gene targeting, Mouse embryo

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