Protease-mediated PRC1 dissociation promotes H2AK119ub remodeling during stress responses.

Chromatin must remain competent for responding rapidly to stress signals. Polycomb repressive complex 1 (PRC1) contributes to chromatin compaction through mono-ubiquitylation of histone H2A at Lys119 (H2AK119ub), yet how PRC1 complexes are dissociated from chromatin is only incompletely understood. Here, we show that the protease CAPN3 promotes rapid dissociation of PRC1 complexes from chromatin in response to stress. Following liver injury or heat shock, CAPN3 becomes activated and proteolyzes non-core PRC1 subunits to release the complexes from chromatin, leading to a reduction of H2AK119ub levels. These findings demonstrate that CAPN3 facilitates the remodeling of the chromatin landscape, unveiling a protease-mediated epigenetic mechanism for chromatin remodeling, and reveal CAPN3 as a key regulator of stress-induced epigenetic responses.