Epigenetic regulation via chromatin modulation plays pivotal roles in regulating neural stem cells (NSCs) both during embryonic development and in adult neurogenesis (Yao et al., 2016). One classic epigenetic mechanism is covalent post-translational modifications to histone proteins, including methylation, phosphorylation, acetylation, ubiquitination, and sumoylation. In particular, methylation of histone H3 at K4 and K27 positions act antagonistically to maintain active and repressed gene expression states, respectively. Although it is established that gene expression regulated by H3K27 methylation is one of the major determinants of the capacity of NSCs for either self-renewal or lineage differentiation, little is known about the role of H3K4 methylation in NSC regulation (Albert and Huttner, 2018). In the current issue, Shah et al. (2019) show that Dpy30 and H3K4 methylation are essential for proliferation and differentiation of postnatal NSCs.