DNA methylation and demethylation shape sexual differentiation of neurochemical phenotype

Some of the best-studied neural sex differences depend on differential cell death in males and females, but other sex differences persist even if cell death is prevented. These include sex differences in neurochemical phenotype (i.e., stable patterns of gene expression). Work in our laboratory over the last several years has tested the hypothesis that sex differences in DNA methylation early in life underlie sexual differentiation of neuronal phenotype. We have shown that 1) expression of enzymes that place or remove DNA methylation marks is greatest during the first week of life in the mouse brain and overlaps with the perinatal critical period of sexual differentiation; 2) a transient inhibition of DNA methylation during neonatal life abolishes several sex differences in cell phenotype in the mouse hypothalamus; 3) both DNA methylation and de-methylation contribute to the development of neural sex differences; and 4) the effects of DNA methylation and de-methylation are brain region- and cell type-specific. •We review evidence that sexual differentiation of hypothalamic cell types depends on DNA methylation.•DNA methylation writers/erasers are most abundant neonatally, suggesting a role in brain development.•Inhibiting DNA methylation affects ERα expression in a sex- and region-specific manner.•To our knowledge, we are the first to tie DNA demethylation to sexual differentiation.