PHF19 drives PRC2 sub-nuclear compartmentalization to promote motility in TNBC cells

Polycomb Repressive Complex 2 (PRC2) is a key regulator of chromatin architecture and transcriptional repression, playing essential roles in development and disease. While its enzymatic activity is well characterized, the molecular factors governing PRC2 subnuclear organization, particularly in cancer cells, are largely unknown. Here, we integrate high-resolution in situ spatial proteomics, imaging, and functional genomics to investigate PRC2 compartmentalization in triple-negative breast cancer (TNBC) cells. We identify PHF19, a sub-stoichiometric PRC2 accessory subunit upregulated in TNBC, as a key factor driving the formation of micron-sized nuclear PRC2 bodies. These structures act as functional hubs that stabilize PRC2 occupancy and reinforce H3K27me3 domain organization. Mechanistically, we identify an intrinsically disordered region (IDR) within PHF19 that is essential for its clustering behavior in cells and link this property to the role of PHF19 in promoting cancer cell motility. Our findings uncover a non-enzymatic layer of PRC2 regulation, whereby its local compartmentalization through accessory subunits directly impinges on cellular behavior. These insights expand our understanding of PRC2 spatial biology with implications for both normal development and disease progression.