A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse
Author:
Hoki Yuko1, Kimura Naomi1, Kanbayashi Minako1, Amakawa Yuko12, Ohhata Tatsuya1, Sasaki Hiroyuki12, Sado Takashi12
Affiliation:
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.
Abstract
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.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference33 articles.
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