PCGF1 (polycomb group ring finger 1) is a core component of Polycomb Repressive Complex 1.1 (PRC1.1), functioning as an epigenetic regulator that maintains transcriptional repression through histone H2A monoubiquitylation at lysine 119 (H2AK119ub) 1. Within PRC1.1 complexes containing BCOR and KDM2B, PCGF1 regulates RNF2 ubiquitin ligase activity to mediate chr2 modifications 2. PCGF1 also promotes stemness and proliferation by repressing CDKN1A (cell cycle inhibitor) expression, particularly in colorectal cancer stem cells 3. Disease relevance spans multiple pathologies: in acute myeloid leukemia with KMT2A rearrangements, loss of PRC1.1 subunits including PCGF1 causes menin inhibitor resistance through reactivation of oncogenic targets like MYC 2; in adolescent depression, reduced microglial PCGF1 correlates with neuroinflammation through MMP10 upregulation and NF-κB/MAPK pathway activation 4; and in bone loss, PRC1.1 acts as an epigenetic brake suppressing Wnt signaling 1. Therapeutically, PCGF1 represents a druggable target—small molecule inhibitors of BCOR-PCGF1 interaction enhance bone formation, while PCGF1 inhibition combined with venetoclax or MYC inhibition may overcome leukemia resistance 21. Additionally, PCGF1 functions in developmental gene licensing through SKP1A-mediated PRC2 degradation, preconditioning genes for activation 5.