Polycomb repressive complex 1.1 orchestrates homeostatic and emergency hematopoiesis and restricts transformation by acting as a rheostat of myelopoiesis

Polycomb repressive complex (PRC) 1 negatively regulates transcription of target genes by mono-ubiquitination of histone H2A at lysine 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 PRC1.1 does not affect self-renewal of HSCs, but restricts myeloid transcriptional program to orchestrates homeostatic as well as emergency hematopoiesis. The deletion of Pcgf1, encoding a core PRC1.1 component, in mice showed active myelopoiesis mimicking emergency myelopoiesis with constitutive expansion of granulocyte-macrophage progenitors (GMPs), and eventually developed lethal myeloproliferative neoplasms. PRC1.1 appeared to target myeloid regulator genes, such as Cebpa and Hoxa9, in lineage commitment of hematopoietic stem and progenitor cells and GMP self-renewal, respectively, to attenuate their expression. Collectively, our findings uncover that PRC1.1 is a novel negative regulator of myelopoiesis, thereby serving as a critical rheostat of emergency myelopoiesis and myeloid transformation.