Epigenetic activation of mouse ganglioside synthase genes: implications for neurogenesis.

The quantity and expression pattern of gangliosides in mammalian brain change drastically during development and are mainly regulated through stage-specific expression of ganglioside synthase genes. Despite extensive investigations in the past, it remains largely unclear how the transcriptional activation of the genes encoding glycosyltransferases is regulated. Here, we show that in the neuronogenic cultures of mouse embryonic brain-derived neuroepithelial cells, histone modifications including acetylated histone H3 and histone H4, but not histone H3 trimethylation at lysine 27 of two genes encoding two key regulatory GTs, namely, N-acetylgalactosaminyltransferase I and sialyltransferase II, were extensively and gradually enhanced, respectively. As a consequence, the level of each GT mRNA was increased correspondingly. Hyperacetylation of histones on the GalNAcT promoter resulted in recruitment of the trans-activation factors Sp2 and AP-1 when cellular histone deacetylases 1 and 2 were knocked down with RNA interference or inhibited by treatment with valproic acid. Moreover, epigenetic activation of GalNAcT was also detected, as accompanied by a pronounced induction of neural differentiation in primary neuroepithelium culture responding to an exogenous supplement of ganglioside GM1, a downstream product of the gene's encoding enzyme. Our findings thus provide direct evidence of novel pathways for ganglioside expression via the epigenetic up-regulation of ganglioside synthase genes during neural development.