Epigenetic Underpinnings of Developmental Sex Differences in the Brain

Sexual differentiation of the brain is a crucial developmental process that enables the lifelong expression of sexually dimorphic behaviors, including those necessary for successful reproduction. During a perinatal sensitive period, gonadal hormones defeminize and masculinize the male brain, and a lack of gonadal steroids allows for feminization in the female. This hormonally-induced differentiation permanently alters neural structures, creating highly dimorphic brain regions; however, the mechanism by which hormones exert their long-lasting effects are still largely unknown. Epigenetic processes such as DNA methylation and histone modifications serve as an interface for environmental stimuli to exert control over the genome. These modifications have the capacity to activate or repress gene expression, thereby shaping the developmental outcomes of cells, circuits, and structures in the brain. Sex differences in methylation, methyl-binding proteins, and chromatin modifications indicate that epigenetic mechanism may be important for sexual differentiation of the brain. The data outlined in this review provide evidence that gonadal hormones in the neonatal brain influence epigenetic processes such as DNA methylation and histone acetylation, but also emphasize the primitive status of our current understanding of epigenetics and sexual differentiation and the brain.