PHF19 drives the formation of PRC2 clusters to enhance motility in TNBC cells

Polycomb repressive complex 2 (PRC2) is a key regulator of transcriptional repression and chromatin organization, essential in development and disease. While its enzymatic activity is well characterized, the factors governing PRC2 subnuclear organization, particularly in cancer cells, are largely unknown. Here, we integrate in situ subcellular proteomics, high-resolution imaging, and functional genomics to investigate PRC2 compartmentalization in triple-negative breast cancer (TNBC) cells. We identify PHF19, a sub-stoichiometric PRC2 accessory subunit, as upregulated in TNBC and central to the formation of endogenous, micron-scale nuclear PRC2 clusters. These structures act as spatial hubs that stabilize local PRC2 occupancy and reinforce H3K27me3 macro-domain organization. Mechanistically, an intrinsically disordered region (IDR) in PHF19 is required for clustering and promoting TNBC cell motility. Our findings uncover a non-enzymatic layer of PRC2 regulation, where local PRC2 compartmentalization through accessory subunits, directly influences cellular behavior, with implications for disease and development.