ABSTRACT
It remains unknown whether H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem and progenitor cells (NSCs and NPCs, or NSPCs). Here we show that the Dpy30 subunit of the major H3K4 methyltransferase complexes is preferentially expressed at a high level in NSCs and NPCs. By genetically inactivating Dpy30 in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs. Dpy30 inactivation results in deficiency in global H3K4 methylation, and disrupts development of hippocampus and especially the dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. By in vitro assays on neurospheres from mouse brains as well as human and mouse NPCs, we show that Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner, and also enables the differentiation of mouse and human NPCs to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs, and may have implications in neurodevelopmental disorders.
SIGNIFICANCE STATEMENT As a highly prominent epigenetic mark that is associated with gene activation and a number of neurodevelopmental disorders in human, the role of histone H3K4 methylation in the fate determination of neural stem cells is unclear. Result of this study uncover a profound role of this epigenetic modification in the fundamental properties of postnatal neural stem cells, including self-renewal and differentiation, and may have implications for a better understanding and treatment of a broad spectrum of neurodevelopmental disorders associated with H3K4 methylation modulators.
