Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation

The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss of function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin-dependent kinase 1 ( cdk1 ) and Wnt pathway transcriptional co-activator earthbound1/jerky ( ebd1 ). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7 -depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development. Synopsis Histone monomethyl transferase Pr-set7 is required for Drosophila neural stem cells to exit from quiescence. Pr-set7 promotes stem cell reactivation by upregulating the cell cycle regulator Cdk1 and the Wnt pathway transcriptional co-activator Ebd1. Histone monomethyl transferase Pr-set7 promotes cell cycle re-entry of Drosophila neural stem cells from quiescence. Pr-set7 binds to the promoter region of Cdk1 and the Wnt pathway transcriptional co-activator Ebd1 in neural stem cells. Pr-set7 functions upstream of cdk1 and ebd1 to promote neural stem cell reactivation. Graphical Abstract Histone monomethyl transferase Pr-set7 is required for Drosophila neural stem cells to exit from quiescence. Pr-set7 promotes stem cell reactivation by upregulating the cell cycle regulator Cdk1 and the Wnt pathway transcriptional co-activator Ebd1.