Bone morphogenetic protein 4 reduces global H3K4me3 to inhibit proliferation and promote differentiation of human neural stem cells

Abstract

Posttranslational modifications (PTMs) on histone tails spatiotemporally dictate mammalian neural stem cell (NSC) fate. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor {beta} (TGF-{beta}) superfamily, suppresses NSC proliferation and fosters differentiation into astroglial cells. Whether PTMs mediate these effects of BMP4 is unknown. Here we demonstrate that BMP4 signaling causes a net reduction in cellular histone H3 lysine 4 trimethylation (H3K4me3), an active histone mark at promoters of genes associated with human NSC proliferation. We also show that H3K4me3 reduction by BMP4 is mediated by decreased expression of SETD1A and WDR82, two methyltransferase components of SETD1A-COMPASS. Down-regulation of these components decreases expression of key genes expressed in hNSCs, while ectopic expression via transfection dedifferentiates human astrocytes (HAs). These observations suggest that BMP4 influences NSC fate by regulating PTMs and altering chromatin structure. SIGNIFICANCE STATEMENTBMP4 is critical in determining hNSC fate. Whether histone posttranslational modifications (PTM) mediate the effects of BMP4 is unknown. Here we report that H3K4me3, brought about by its methyltransferases SETD1A and WDR82, at promoters of stem cell genes OCT4 and NESTIN is involved in human neural stem cell (hNSC) maintenance. BMP4 promotes hNSC astroglial differentiation in part through reduction of SETD1A and WDR82 and thus decreased frequency of H3K4me3 at the promoters of these genes. These results provide evidence that BMP4 promotes hNSC differentiation through a potential epigenetic mechanism and extend our understanding of the role of histone PTM in central nervous system development.