Chapter 10 - Regulation of PRC2 Activity

Abstract

Polycomb repressive complex 2 (PRC2) plays a vital role during development. It is responsible for establishing and maintaining the repressive states of thousands of developmental genes. The function of PRC2 is primarily attributed to its methyltransferase activity toward H3K27, and aberrant activation or inhibition of PRC2 activity is often linked to cancer. To ensure the proper function of PRC2, various mechanisms are exploited to modulate its enzymatic activity. Repressive histone modifications and dense chromatin robustly stimulate PRC2 activity to achieve efficient establishment and maintenance of H3K27 methylation, whereas active chromatin inhibits PRC2 to prevent the spreading of H3K27 methylation into transcribed genes. PRC2 activity is also modulated by different accessory subunits. These mechanisms provide multiple dimensions of regulation and ensure the robustness and versatility of PRC2 activity. In this chapter, we will summarize these regulatory mechanisms and discuss how they contribute to the physiological functions of PRC2. In addition, we will highlight recent findings on a recurrent H3K27M mutation in pediatric glioblastomas (GBMs) that inhibits the PRC2 complex and envision how these studies may help in treating GBM.