DNMT3a and DNMT1, for de novo and maintenance DNA methylation respectively, adopted a program distinct from the histone marks. Their activities increased at the beginning of differentiation, as indicated by contrasting the core and peripheral zones of the neurosphere. The expression of these two DNA methylating enzymes is higher in the periphery ring than in the core of the neurosphere during early differentiation. This suggests an increase in de novo and maintenance of DNA methylation just prior to differentiation. A characteristic expression level of DNMT1 for maintenance of DNA methylation in the differentiating neurosphere was found, as indicated by the high-expression ring formed by DNMT1-im in the periphery of neurosphere (Figure 1D). This development supports the notion that a larger population of genes is suppressed during differentiation into restricted cell types. Genome-wide gene expression analysis revealed that mouse stem cells, such as embryonic stem cells and neural stem cells, express approximately 40-60% of the total genes in a genome; in contrast, most differentiated cells express only 10-20% of the total genes (1,4). Further, as we demonstrated, the rise of these
