Sex-specific silencing of X-linked genes by Xist RNA.

ABSTRACT: X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of X(?Tsix)Y male cells displayed ectopic Xist RNA coating compared with X(?Tsix)X female cells. This increase reflected the inability of X(?Tsix)Y cells to efficiently silence X-linked genes compared with X(?Tsix)X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X(?Tsix)X female cells relative to X(?Tsix)Y male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating X(?Tsix)Y and 39,X(?Tsix) (X(?Tsix)O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because X(?Tsix)X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X(?Tsix) X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing.

SUBMITTER: Gayen S 

PROVIDER: S-EPMC4725534 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature