PRC2 insufficiency causes p53-dependent dyserythropoiesis

Ezh1 and Ezh2 are the enzymatic components of Polycomb repressive complex (PRC) 2, which catalyzes histone H3K27 tri-methylation (H3K27me3) to repress transcription of PRC2 target genes. We previously reported that the hematopoietic cell-specific Ezh2 deletion (Ezh2d/d) induces a myelodysplastic syndrome (MDS)-like disease in mice. We herein demonstrated that severe PRC2 insufficiency induced by the one allele deletion of Ezh1 in Ezh2-deficient mice (Ezh1+/-Ezh2d/d) caused advanced macrocytic anemia accompanied by a differentiation block and enhanced apoptosis in erythroblasts. p53, which is activated in del(5q) MDS, was specifically activated in erythroblasts but not in hematopoietic stem and progenitor cells in Ezh1+/-Ezh2d/d mice. Cdkn2a, a major PRC2 target encoding p19Arf, which activates p53 by inhibiting MDM2 E3 ubiquitin ligase, was de-repressed in Ezh1+/-Ezh2d/d erythroblast. The deletion of Cdkn2a as well as p53 rescued dyserythropoiesis in Ezh1+/-Ezh2d/d mice, indicating that PRC2 insufficiency caused p53-dependent dyserythropoiesis via de-repression of Cdkn2a. Protein synthesis was attenuated in Ezh1+/-Ezh2d/d erythroblasts, suggesting impaired ribosomal biogenesis that contributes to full activation of p53 by Arf. Since PRC2 insufficiency is often involved in the pathogenesis of MDS, our findings suggest that p53-dependent dyserythropoiesis manifests not only in del(5q) MDS but also other types of MDS in a setting of PRC2 insufficiency.