A methylation-phosphorylation switch controls EZH2 stability and hematopoiesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38346162.
- Also identified by DOI 10.7554/eLife.86168 and PMC identifier 10901513.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 mouse <i>Kdm1a</i> deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of <i>L3mbtl3</i> or <i>Dcaf5</i> results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4<sup>DCAF5</sup> ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse <i>Ezh2</i><sup>K20R/K20R</sup> mutants develop hepatosplenomegaly associated with high GFI1B expression, and <i>Ezh2</i><sup>K20R/K20R</sup> 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 regulate the PRC2 activity and hematopoiesis.
Medical subject headings
- DNA-Binding Proteins
- Histones