Enhancer of Polycomb maintains germline activity and genome integrity in Drosophila testis

Tissue homeostasis depends on the activities of tissue-specific adult stem cells to maintain a balance between proliferation and differentiation and ensure DNA damage repair. Here, we use the Drosophila male germline stem cell lineage to study how a chromatin factor, Enhancer of Polycomb [E(Pc)], regulates the proliferation-to-differentiation (mitosis-to-meiosis) transition and DNA damage repair. We identified two critical target genes of E(Pc). First, E(Pc) directly represses CycB transcription through modulating H4 acetylation. Second, E(Pc) is required for accumulation of an important germline differentiation factor, Bag-of-marbles (Bam) protein, through post-transcriptional regulation. When E(Pc) is downregulated, increased CycB transcription and decreased Bam protein are both responsible for defective mitosis-to-meiosis transition in germ cells. Moreover, E(Pc) is required for the DNA double-strand break repair, the failure of which leads to germ cell death. Finally, compromising the activity of Tip60, a histone acetyltransferase, leads to germline defects similar to E(Pc) loss-of-function, suggesting that E(Pc) acts cooperatively with Tip60 . Together, our data demonstrate that E(Pc) has pleiotropic roles in maintaining male germline activity and genome integrity. E(Pc) is highly conserved with implications in cancers; consequently, our findings will help elucidate the in vivo mechanisms of E(Pc), in turn making this chromatin factor a promising target for cancer treatment.