The timing of Ezh2 action in stem cell differentiation

The maintenance of a correct differentiation program is essential for tissue homeostasis and repair. Polycomb group (PcG) proteins mediate the epigenetic silencing of genes and have been implicated in regulating the fate of adult stem cells and their differentiation state. Polycomb repressive complex 2 (PRC2) consists of the four subunits Ezh2, Suz12, EED and RbAp48; Ezh2 is responsible for the trimethylation of lysine 27 of histone H3 (H3K27me3), which transcriptionally represses key factors involved in lineage specification. Studying the role of PRC2 in adult stem cells has been hampered owing to the prenatal lethality of PRC2-subunit knockouts, but satellite cells (the primary muscle stem cells) provide a suitable system to investigate the function of PRC2. Here (p. 565), Jennifer Pell and colleagues use genome-wide histone methylation maps of satellite cells together with two conditional Ezh2-null mouse strains to elucidate the role of Ezh2 in muscle differentiation in vivo. They find that mice lacking Ezh2 in satellite cells show decreased muscle growth and a reduced number of stem cells, whereas, surprisingly, depletion of Ezh2 after the onset of terminal differentiation did not impede muscle repair. Genome-wide H3K27me3 mapping in isolated primary satellite cells confirmed that Ezh2 mediates the silencing of factors associated with lineage specification within a proliferative progenitor population, but not that of genes involved in terminal differentiation.