RNF2 mediates H2A ubiquitination to promote colitis via suppressing monocyte-macrophage transition in mice

Monocyte-macrophage transition is dysregulated in inflammatory bowel disease. While polycomb repressive complexes are crucial for maintaining cellular identity, their specific roles in colitis are poorly defined. Here, we show that Ring finger protein 2, a core catalytic subunit of polycomb repressive complex 1, regulates the monocyte-macrophage transition during colitis. It is highly expressed in the immature colon and circulating monocytes during ulcerative colitis. And mice with myeloid-specific deficiency exhibited attenuated experimental colitis, restored monocyte/macrophage balance, and improved anti-tumor necrosis factor alpha efficacy. Mechanistically, Ring finger protein 2 represses Runt-related transcription factor 3 expression via histone H2A lysine 119 monoubiquitination. This disrupts the inhibition of the recombination signal-binding protein for the immunoglobulin kappa J region, the central activator of the Notch pathway, thereby exacerbating inflammation. Silencing of the axis markedly inhibited proinflammatory responses, regulating monocyte-macrophage transition. These findings reveal that Ring finger protein 2 disrupts the monocyte-macrophage transition during colitis, offering insights into colitis treatments. The cellular differentiation of monocytes to macrophages is perturbed in inflammatory bowel disease. Here, the authors show that RNF2 drives H2A ubiquitination and link this to the immunopathology of colitis by suppressing the monocyte-macrophage transition.