The Drosophila histone methyl-transferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation.

Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of set1 results in temporally progressed defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the set1 knockdown phenotypes, highlighting the functional importance of the methyl-transferase activity of Set1. Further, RNA-seq experiments reveal key signaling pathway components, such as the JAK-STAT pathway stat92E and the BMP pathway mad genes that are upregulated upon set1 knockdown. Genetic interaction assays support the functional relationships between set1 and JAK-STAT or BMP pathways, as both stat92E and mad mutations suppress the set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The germ cell loss followed by over-proliferation phenotype when inhibiting a histone methyl-transferase also raise concerns about using their inhibitors in cancer therapy.