Cdk1 controls global epigenetic landscape in embryonic stem cells

In this study, we found that in ES cells the majority of Cdk1 substrates are localized on chromatin. Cdk1 phosphorylates a large number of proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. High levels of Cdk1 in ES cells phosphorylate and partially inactivate Dot1l, the histone H3 lysine 79 methyltransferase responsible for placing activating H3K79 marks on gene bodies. Decrease of Cdk1 activity during ES cell differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ES cells. Overall design: In mouse embryonic stem cells: (1) Thio-ChIP-seq for the Cdk1 substrates-binding DNA; (2) H3K79me2 ChIP-seq upon Cdk1 inhibition; (3) Transcriptome of WT cells, and WT vs. Dot1l KO cells in SL medium and during Wnt3a and activin A-induced differentiation.