Non-canonical PRC1 orchestrates homeostatic and emergency hematopoiesis and restricts transformation by acting as a rheostat of myeloid differentiation

Polycomb repressive complex (PRC) 1 negatively regulates transcription of target genes by mono-ubiquitylation of histone H2A at lysin 119. While canonical PRC1 has been implicated in the maintenance of hematopoietic stem cells (HSCs), the function of PRC1.1, a variant PRC1 remained elusive. Here we show that the deletion of Pcgf1, encoding a core PRC1.1 component, in mice does not affect self-renewal of HSCs, but prematurely activates myeloid transcriptional programs in hematopoietic stem and progenitor cells, leading to enhanced myeloid commitment and subsequent expansion of myeloid progeny. We identified myeloid regulator genes, such as Cebpa and Hoxa9, are the direct targets of PRC1.1 responsible for active myelopoiesis. Pcgf1-deficient hematopoiesis appeared to recapitulate the emergency myelopoiesis induced by bacterial infection, and eventually evolved into lethal myeloproliferative neoplasms. Collectively, our findings indicate that PRC1.1 restricts myeloid differentiation to maintain homeostatic hematopoiesis, thereby serving as a critical gatekeeper of emergency myelopoiesis and myeloid transformation.