ApoE regulates neurogenesis, although how it influences genetic programs remains elusive. Cortical neurons induced from isogenic control and human neural stem cells (NSCs) recapitulated key transcriptomic signatures of counterparts identified from single-cell human midbrain. Surprisingly, ApoE expression in NSC and neural progenitor cells (NPCs) is not required for differentiation. Instead, ApoE prevents the over-proliferation of non-neuronal cells during extended neuronal culture when it is not expressed. Elevated level in cells lowers the EZH1 protein and the repressive H3K27me3 mark, a phenotype rescued by steric inhibitor. Reduced H3K27me3 at genes linked to extracellular matrix organization and angiogenesis in NPC correlates with their aberrant expression and phenotypes in neurons. Interestingly, the coding sequence, which contains many predicted binding sites, can repress without translating into protein. This suggests that maintains neurons integrity through the target-directed miRNA degradation of , imparting the H3K27me3-mediated repression of non-neuronal genes during differentiation.