A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem cells

It remains largely unclear if efficient H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem cells (NSCs). By inactivating the Dpy30 subunit of the major mammalian H3K4 methyltransferase complexes 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 NSCs. Loss Dpy30 disrupts the development of dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. Dpy30 is indispensable for sustaining the self-renewal of NSCs in a cell-intrinsic manner. Dpy30 also enables the differentiation of mouse and human neural progenitor cells 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 NSCs, and may have implications in neurodevelopmental disorders. Overall design: Samples 1-6 are RNA-seq from Dentate Gyrus (DG) and samples 7-12 are RNA-seq from Subventricular zone (SVZ) from mice of control and KO genotypes.

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Shah K, King GD, Jiang H