Myc regulates the expression of PRC2 to maintain pluripotency of embryonic stem cells

Myc is a key molecule in transformation, cell reprogramming, and its expression is critical to maintain embryonic stem cells (ESC) in the undifferentiated state. However, the mechanism by which Myc performs these tasks has not yet been elucidated. We observed that Myc directly up-regulates all core components of the Polycomb Repressive Complex 2 (PRC2) both in ESC and in differentiated cells. PRC2 is a transcriptional repressive complex that catalyzes histone H3 methylation of Lysine 27 at promoters of developmental regulators contributing to silence their expression. By expressing Myc-ER in fibroblasts we observed that Myc, by recruiting Histone Acetyltransferases (HATs) to the regulatory elements of the core components of PRC2 complex (Suz12, Ezh2, and Eed), induces the acetylation of H3 and H4 and the increase of the elongating RNA Polimerase II at their promoters. Silencing of both c-Myc and N-Myc in ESC induces the reduction of PRC2 expression leading to loss of stemness and reduction of proliferation. Analysis of epigenetic modifications and expression at PRC2 target genes revealed that c-Myc and N-Myc silencing induces the de-repression of ‘bivalent’ developmental regulators by reduction of H3K27me3 signal on their promoters. The ectopic expression of PRC2 in c-Myc and N-Myc silenced ESC restores the H3K27me3 modification at bivalent genes and the ability to form single cell colonies. Thus, Myc proteins contribute to maintain ESC pluripotency by controlling the expression of developmental regulators via the polycomb PRC2 complex.