Epigenetic mechanisms are known to exert control over gene expression and determine cell fate. Genetic mutations in epigenetic regulators are responsible for several neurologic disorders. Mutations of the chromatin remodeling protein Lsh/HELLS can cause the human Immunodeficiency, Centromere instability and Facial anomalies (ICF) syndrome, which is associated with neurologic deficiencies. We report here a critical role for Lsh in murine neural development. Lsh depleted neural stem/progenitor cells (NSPCs) display reduced growth, increases in apoptosis and impaired ability of self-renewal. RNA-seq analysis demonstrates differential gene expression in Lsh−/− NSPCs and suggests multiple aberrant pathways. Concentrating on specific genomic targets, we show that ablation of Lsh alters epigenetic states at specific enhancer regions of the key cell cycle regulator Cdkn1a and the stem cell regulator Bmp4 in NSPCs and alters their expression. These results suggest that Lsh exerts epigenetic regulation at key regulators of neural stem cell fate ensuring adequate NSPCs self-renewal and maintenance during development.