DRP004311
Ezh1 targets bivalent developmental regulator genes to maintain self-renewing stem cells in Ezh2-insufficient myelodysplastic syndrome
Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic cell-specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, while the concurrent deletion of Ezh1, the Ezh2 paralogue gene, abolished hematopoiesis due to the depletion of hematopoietic stem and progenitor cells (HSPCs) as well as MDS stem cells. However, the epigenetic mechanisms underlying maintenance of Ezh2-deficient MDS stem cells by Ezh1 has not been investigated in detail. We herein demonstrated that mice with only one Ezh1 allele (Ezh1+/-Ezh2d/d) maintained functional HSPCs. A ChIP sequence analysis of Ezh1+/-Ezh2d/d HSPCs revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitylation (H2AK119ub1). These core PRC2 targets were mostly bivalent developmental regulator genes, the promoters of which were marked by H3K4me3 and H3K27me3, and maintained H3K27me3 levels even in Ezh1+/-Ezh2d/d HSPCs. Upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of core PRC2 target genes were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of PRC2 in HSCs as well as MDS stem cells.