Epigenetic mechanisms are involved in sexual differentiation of the brain

Abstract

Sexual differentiation of the brain can be considered as a process during which effects of sex steroid hormones secreted during early development is maintained into adulthood. Epigenetic regulation is emerging as a potentially important mechanism of conveyance of long-lasting effects of the hormonal and environmental milieu in the developing brain. Evidence has accumulated to show that epigenetic regulation is involved in the control of sexual differentiation of the brain. In the preoptic area (POA), which is important for male sexual behavior, histones associated with the estrogen receptor (ER) α and aromatase (Arom) gene promoters are differentially acetylated between the sexes, and two subtypes of histone deacetylase (HDAC2 and 4) are associated with the same promoters at higher frequencies in males in the early postnatal period. Since ERα and Arom are essential genes in masculinization of the brain, these findings suggest that histone deacetylation in the early postnatal period is involved in masculinization of the brain. Indeed, inhibition of HDAC activity in males during this period abrogates brain masculinization: structural sexual dimorphism of the bed nucleus of the stria terminalis is eliminated and expression of male sexual behavior is reduced in adulthood. Previous reports have demonstrated that ERα gene expression in the POA is higher in females during the developmental and pubertal periods and in adulthood, indicating that sexually dimorphic ERα expression that appears in early postnatal development is maintained until adulthood by epigenetic programming. The ERα promoter is also more sparsely methylated in females, with an inverse correlation with ERα expression. In addition to the hormonal effect, the amount of maternal care received during postnatal development has a lasting effect on ERα expression mediated by DNA methylation of its promoter. Taken together, these results suggest that epigenetic mechanisms play a central role in the transduction and maintenance of early hormonal and social cues to organize sexually differentiated brain functions.