A role for cyclin dependent kinase Cdk8 in the mammalian dosage compensation system
Cyclin dependent kinases are important cellular regulators and drug targets for a number of diseases. Now a specific function of Cdk8 for gene repression in X chromosome inactivation has been characterized. This finding advances our understanding of the cellular mechanism for dynamic gene regulation by Cdk8.
In mammals, one of the two X chromosomes in female cells is transcriptionally inactive. Therefore a single X is active in females and in males, who possess one X and one Y chromosome, along with two complete sets of autosomes. The coordinated silencing of nearly all genes on the inactive X chromosome is a remarkable process and has become an important paradigm for studying gene regulation in mammals. A better understanding of the molecular mechanism of X chromosome inactivation results from the recent identification of candidate silencing factors. The first indication for an involvement of the atypical cyclin dependent kinase Cdk8 was obtained by forward genetic screening using an advanced cell system of haploid mouse embryonic stem cells (Monfort et al., 2015; highlighted earlier in ETH News). The present study characterized the role of Cdk8 at the initiation of X chromosome inactivation in mice. The results show that loss of Cdk8 leads to incomplete silencing of genes on the inactive X chromosome. In mice, Cdk8 is an essential gene, whose mutation lead to a more severe phenotype in female embryos. The observation of a female specific phenotypic component further supports a requirement of Cdk8 for X chromosome inactivation. Cdk8 has been associated with the mediator complex and is an important mediator kinase. Investigation of Cdk8 function is therefore important for understanding gene regulation in mammalian development and disease.
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