Novel insights into the dynamic function of PRC2 in innate immunity.

The polycomb repressive complex 2 (PRC2) is an established therapeutic target in cancer. PRC2 catalyzes methylation of histone H3 at lysine 27 (H3K27me3) and is known for maintaining eukaryote cell identity. Recent discoveries show that modulation of PRC2 not only impacts cell differentiation and tumor growth but also has immunomodulatory properties. Here, we integrate multiple immunological fields to understand PRC2 and its subunits in epigenetic canonical regulation and non-canonical mechanisms within innate immunity. We discuss how PRC2 regulates hematopoietic stem cell proliferation, myeloid cell differentiation, and shapes innate immune responses. The PRC2 catalytic domain EZH2 is upregulated in various human inflammatory diseases and its deletion or inhibition in experimental mouse models can reduce disease severity, emphasizing its importance in regulating inflammation.