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Published on: May 12, 2017
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Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.
Wojciech Michowski1, Joel M Chick2, Chen Chu3
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Molecular Cell
|April 3, 2020
Summary
Cyclin-dependent kinase 1 (Cdk1) maintains the epigenetic identity of embryonic stem cells (ESCs). Cdk1 phosphorylates key epigenetic regulators, influencing histone modifications and gene expression during differentiation.
Area of Science:
- Cell Biology
- Epigenetics
- Molecular Biology
Background:
- Cyclin-dependent kinase 1 (Cdk1) is a key regulator of cell division.
- Embryonic stem cells (ESCs) exhibit high Cdk1 activity, suggesting roles beyond cell cycle progression.
- Understanding Cdk1's broader functions is crucial for stem cell biology and developmental processes.
Purpose of the Study:
- To investigate non-canonical functions of Cdk1 in ESCs.
- To identify Cdk1 substrates involved in epigenetic regulation within ESCs.
- To elucidate Cdk1's role in maintaining ESC epigenetic identity and its modulation during differentiation.
Main Methods:
- Generation of knockin mice expressing analog-sensitive Cdk1.
- Analysis of Cdk1 substrates localized on chromatin in ESCs.
- Assessment of histone modification changes upon Cdk1 inhibition and during ESC differentiation.
Main Results:
- A significant portion of Cdk1 substrates in ESCs are chromatin-associated.
- Cdk1 phosphorylates numerous epigenetic regulators, including histone mark writers and erasers.
- Cdk1 activity in ESCs partially inactivates Dot1l, a histone methyltransferase, affecting H3K79 methylation.
- Reduced Cdk1 activity during differentiation de-represses Dot1l, facilitating differentiation gene expression.
Conclusions:
- Cdk1 plays a critical role in maintaining the epigenetic landscape of ESCs.
- Cdk1-mediated phosphorylation of epigenetic modifiers like Dot1l is essential for preserving ESC identity.
- Modulation of Cdk1 activity is integral to the transition from ESCs to differentiated cells, involving epigenetic reprogramming.
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