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A bstract   Histone‐modifying enzymes dynamically regulate the chromatin status and have been implicated in the fate specification of stem cells, including neural stem cells (NSCs), which differentiate into three major cell types: neurons, astrocytes, and oligodendrocytes. Lysine‐specific demethylase 1 (LSD1, also known as KDM1A) catalyzes the demethylation of H3K4me1/2 and H3K9me1/2, and it was recently suggested that functional disruption of LSD1 links to various human diseases. However, the mechanism by which LSD1 regulates human neural development remains unclear. Here, we present evidence that specific inhibition of LSD1 suppresses the neurogenesis of cultured human fetal NSCs (hfNSCs) isolated from the human fetal neocortex. Notably, we found that LSD1 directly associates with the promoter of the  HEYL  gene, and controls the demethylation of H3K4me2, which is accompanied by repression of  HEYL  expression during hfNSC neuronal differentiation. Furthermore, we also showed that HEYL expression is sufficient to inhibit the neuronal differentiation of hfNSCs. This mechanism seems to be primate‐specific because mouse NSCs do not exhibit the LSD1 inhibitor‐induced upregulation of  Heyl . Our findings suggest that LSD1 plays an important role in primate neurogenesis and may contribute to the characterization of an evolved primate brain. S tem  C ells   2016;34:1872–1882

LSD1 Mediates Neuronal Differentiation of Human Fetal Neural Stem Cells by Controlling the Expression of a Novel Target Gene, HEYL