Differentiating Drosophila female germ cells initiate Polycomb silencing by altering PRC2 sampling

Summary Polycomb silencing represses gene expression and provides a molecular memory of chromatin state that is essential for animal development. We show that Drosophila female germline stem cells (GSCs) provide a powerful system for studying Polycomb silencing and how it is established. GSCs resemble pluripotent mammalian embryonic cells in lacking silenced chromatin, but most GSC daughters, like typical somatic cells, induce Polycomb silencing as they differentiate into nurse cells. Developmentally controlled changes in the levels of two Polycomb repressive complex 2 (PRC2)-interacting proteins, Pcl and Scm, initiate differentiation. In germline stem cells, abundant Pcl inhibits silencing by slowing PRC2 and diverting it from PRE sequences. During differentiation, core PRC2 represses inactive loci while Scm and residual Pcl cooperate to enrich PRC2 and silence traditional Polycomb domains. We propose that PRC2-interacting proteins regulate the transition from a variable to stable transcription state during differentiation by altering the rate that PRC2 samples regulatory sequences.