Evidence of Xist RNA-independent initiation of mouse imprinted X-chromosome inactivation

Open Access
Publisher Website
Google Scholar
Abstract
Female mammals carry two copies of the X chromosome, compared to the one X and one Y of the male, and to counter the potentially toxic effect of a double-dose of a gene, most of the genes on one X chromosome are silenced. This process of X-chromosome inactivation (XCI) has long been assumed to be triggered by the expression of the RNA gene Xist, specifically the copy on the inactive X chromosome. New work on embryos of mice engineered to contain a defective Xist gene on their future inactive X chromosome reveals a more complicated picture. In fact, silencing of the paternal X chromosome during imprinted XCI can be initiated in the absence of paternal Xist. In the continued absence of Xist the X chromosome eventually reactivates, suggesting that its role may be to stabilize silencing over the long term. Female mammals undergo silencing of most genes on one of their two X chromosomes in a process termed X-chromosome inactivation (XCI). In placental mammals, the non-coding RNA Xist is thought to trigger XCI. Here it is demonstrated that silencing of the paternal X chromosome (Xp) is able to initiate in the absence of paternal Xist; Xist is, however, required to stabilize silencing along the Xp. XX female mammals undergo transcriptional silencing of most genes on one of their two X chromosomes to equalize X-linked gene dosage with XY males in a process referred to as X-chromosome inactivation (XCI). XCI is an example of epigenetic regulation1. Once enacted in individual cells of the early female embryo, XCI is stably transmitted such that most descendant cells maintain silencing of that X chromosome2. In eutherian mammals, XCI is thought to be triggered by the expression of the non-coding Xist RNA from the future inactive X chromosome (Xi)3,4,5; Xist RNA in turn is proposed to recruit protein complexes that bring about heterochromatinization of the Xi6,7. Here we test whether imprinted XCI, which results in preferential inactivation of the paternal X chromosome (Xp), occurs in mouse embryos inheriting an Xp lacking Xist. We find that silencing of Xp-linked genes can initiate in the absence of paternal Xist; Xist is, however, required to stabilize silencing along the Xp. Xp-linked gene silencing associated with mouse imprinted XCI, therefore, can initiate in the embryo independently of Xist RNA.