ApoE maintains neuronal integrity via miRNA and H3K27me3-mediated repression [miRNA-seq]

To better understand the regulatory roles of ApoE in neurogenesis, we differentiated isogenic control and ApoE-/- human neural stem cells (NSC) into mature cortical neurons and cultured them for additional three weeks. In this study, we found that ApoE is only expressed in control NSC and neural progenitor cell (NPC) stages, but not in mature neurons, suggesting that ApoE may epigenetically regulate the integrity and maintenance of the mature neurons. Mechanistic studies revealed that absence of ApoE in NSC led to upregulation of certain microRNAs, including miR-199a-5p. These microRNAs targeted EZH1 to reduce its protein expression, resulting in the lower level of repressive H3K27me3 marks in ApoE-/- NPC and mature neurons. Chromatin immunoprecipitation experiments suggests that the lower level of H3K27me3 at various extracellular matrix organization and angiogenesis genes is responsible for their higher expression and aberrant phenotypes observed in ApoE-/- neurons. Taken together, our results indicate that ApoE maintains pure population of mature neurons via H3K27me3-mediated repression of genes that drive non-neuronal cell proliferation in NPC stage. Overall design: RNA-seq of poly-A and small RNA in neural stem cells and neurons