Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells

Mol Cell. 2020 May 7;78(3):459-476.e13. doi: 10.1016/j.molcel.2020.03.010. Epub 2020 Apr 1.


The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.

Keywords: analog sensitive kinase; cell cycle; cyclin; cyclin dependent kinase; differentiation; embryonic stem cells; epigenetics; phosphoproteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / metabolism
  • Animals
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin Immunoprecipitation / methods
  • Embryonic Stem Cells / physiology*
  • Epigenesis, Genetic*
  • Female
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Saccharomyces cerevisiae Proteins / metabolism


  • Saccharomyces cerevisiae Proteins
  • adenosine 5'-O-(3-thiotriphosphate)
  • Adenosine Triphosphate
  • Dot1l protein, mouse
  • Histone-Lysine N-Methyltransferase
  • CDC2 Protein Kinase
  • Cdk1 protein, mouse