Mammalian development is associated with considerable changes in global DNA methylation levels during genomic reprogramming. The current genome-wide methylation study, showing widespread DNA methylation changes in specific genes of NSCs, supports our previous observation that DNA methylation is an active component and an intrinsic program during differentiation of NSCs (Singh et al., 2009a). In particular, we observed hyper- and hypo-methylation of moderately methylated genes during the reprogramming of quiescent NSCs into differentiation. There are two major questions addressed in this study: first, whether altered DNA methylation in the process of neural stem cell differentiation can be modified by the environmental input, i.e. whether alcohol, which is known to change methyl donor, can alter the intrinsic DNA methylation program during differentiation. Second, whether the altered DNA methylation (by alcohol) has a functional consequence on neural stem cell development. Two categories of alcohol effect are reported here. First, alcohol prevented programmed diversification of DNA methylation during differentiation, i.e. it prevented moderately methylated genes from increased or decreased methylation, or further, becoming significantly hyper- or hypo-methylated. As promoter DNA methylation represses transcription and
