mSWI/SNF promotes distal repression by titrating polycomb dosage

The mammalian SWI/SNF, or BAF complex, has a conserved and direct role in antagonizing polycomb-mediated repression. Yet, BAF appears to also promote repression by polycomb in stem cells and cancer. How BAF both antagonizes and promotes polycomb-mediated repression remains unknown. Here, we utilize targeted protein degradation to dissect the BAF-polycomb axis in embryonic stem cells on the timescale of hours. We report that rapid BAF depletion leads to quick redistribution of both PRC1 and PRC2 complexes from highly occupied domains, like Hox clusters, to weakly occupied sites genome-wide. This results in transcriptional derepression, chromatin decompaction, and opposite epigenomic changes to repressed domains. Surprisingly, we find that limiting polycomb dosage underlies these effects, such that BAF driven polycomb antagonism titrates the dosage required for repression, reconciling the opposing roles. These findings provide an explanation for the frequent mutation of BAF subunits in neurodevelopmental disorders and certain cancers.