A Methylation-Phosphorylation Switch Controls EZH2 Stability and Hematopoiesis

The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouseLsd1/Kdm1adeletion causes dramatic reduction of PRC2 proteins, whereas mouse null mutation ofL3mbtl3orDcaf5results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is mono-methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4^DCAF5ubiquitin ligase. LSD1 demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to control the PRC2 activity and hematopoiesis.