Cdk8 is required for establishment of chromatin marks and gene repression by Xist and mouse embryonic lineage development

We previously reported the cyclin dependent kinase Cdk8 as a putative silencing factor for Xist. Here we investigate the role of Cdk8 in X inactivation and embryo development. We engineered a Cdk8 mutation in mouse embryonic stem cells carrying an inducible system for studying Xist function. We find that Xist repressed X-linked genes to half the expression level of the active X chromosome in the absence of Cdk8, whereas near complete silencing was observed in cells with intact Cdk8. The reduced ability of Xist to repress genes is paralleled with reduced Ezh2 recruitment and establishment of histone H3 lysine 27 tri-methylation. Introduction of wild-type but not catalytically inactive Cdk8 transgenes restores efficient gene repression and PRC2 recruitment. Notably, mutation of the highly homologous kinase Cdk19 does not affect Xist function. Combined mutations of Cdk8 and Cdk19 resemble the Cdk8 single mutation. Analysis of a conditional Cdk8 mutation in mice reveals a post-implantation lethal phenotype with variable onset between day 8.5 and 10.5. A clear female specific phenotype is masked by requirements of Cdk8 for processes in addition to X inactivation. Differential Gene expression upon Xist expression in the presence and absence of Cdk8 in mouse embryonic stem cells