Cdk8 is required for establishment of H3K27me3 and gene repression by Xist and mouse development

We previously identified the cyclin dependent kinase Cdk8 as a putative silencing factor for Xist. To investigate its role in X inactivation, we engineered a Cdk8 mutation in mouse embryonic stem cells (ESCs) carrying an inducible system for studying Xist function. We find that Xist represses X-linked genes to half the expression level in Cdk8 mutant cells, whereas near complete silencing is observed in controls. Lack of Cdk8 impairs Ezh2 recruitment and establishment of histone H3 lysine 27 tri-methylation but not PRC1 recruitment by Xist. Transgenic expression of wild-type but not catalytically inactive Cdk8 restores efficient gene repression and PRC2 recruitment. Mutation of the paralogous kinase Cdk19 does not affect Xist function and combined mutations of Cdk8 and Cdk19 resemble the Cdk8 mutation. In mice a Cdk8 mutation causes post-implantation lethality. We observe that homozygous Cdk8 mutant female embryos show a greater developmental delay than males on day 10.5. Together with ...