A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis.

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Biology

Background:

• Polycomb Repressive Complex 2 (PRC2) is crucial for development and cell fate, regulating gene expression via H3K27 methylation.
• Dysregulation of PRC2 is implicated in various cancers.

Purpose of the Study:

• To investigate the regulatory mechanisms controlling PRC2 protein levels and activity.
• To elucidate the role of EZH2 post-translational modifications in PRC2 function and hematopoiesis.

Main Methods:

• Utilized mouse models with genetic alterations in Kdm1a, L3mbtl3, and Dcaf5.
• Investigated EZH2 methylation at K20 and its interaction with L3MBTL3 and CLR4^DCAF5.
• Analyzed the effect of AKT-mediated phosphorylation at EZH2 S21.
• Studied EZH2 K20R mutant mice to assess effects on hematopoiesis.

Main Results:

• Kdm1a deletion reduced PRC2, while L3mbtl3 or Dcaf5 deficiency increased PRC2 and H3K27 trimethylation.
• EZH2 K20 methylation targets it for proteolysis by L3MBTL3/CLR4^DCAF5.
• KDM1A (LSD1) demethylates EZH2 K20, stabilizing EZH2.
• AKT-mediated S21 phosphorylation inhibits EZH2 K20 methylation.
• Ezh2^K20R/K20R mutants exhibited hepatosplenomegaly, increased GFI1B, and hematopoietic stem cell expansion.

Conclusions:

• EZH2 is regulated by methylation-dependent proteolysis, controlled by a methylation-phosphorylation switch involving K20 methylation and S21 phosphorylation.
• This regulatory mechanism fine-tunes PRC2 activity and is critical for normal hematopoiesis.