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 mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 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 CLR4DCAF5 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 Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/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 regulate the PRC2 activity and hematopoiesis.

Pre-workout Induced Demand Ischemia.

Pre-workout supplement use has increased in recent years. Multiple side effects and off-labeled substances have been reported. We report a case of a 35-year-old patient who recently started a pre-workout and was found to have sinus tachycardia, elevated troponin, and subclinical hyperthyroidism. The echocardiogram showed normal ejection fraction and no wall motion abnormality. Beta-blockade therapy with propranolol was offered, but she refused, and her symptoms and troponin levels improved after proper hydration within 36 hours. A cautious and accurate assessment of young, fitness-enthusiastic patients experiencing unusual chest pain is essential to identify a reversible cardiac injury and possible off-label substances in over-the-counter supplements.