Past, present and future of epigenetics in brain sexual differentiation

Sexual differentiation has long been considered "epigenetic", although the meaning of that word has shifted over time. Here, we track the evolution of ideas about epigenetics in sexual differentiation, and identify principles that have emerged from recent studies. Experiments manipulating a particular epigenetic mechanism during neonatal life demonstrate a role for both histone acetylation and DNA methylation in the development of sex differences in the brain and behaviour of rodents. In addition, hormone-dependent sex differences in the number of neurones of a particular phenotype may be programmed by differences in DNA methylation early in life. Genome-wide studies suggest that many effects of neonatal testosterone on the brain methylome do not emerge until adulthood, and there may be sex biases in the use of epigenetic marks that do not correlate with differences in gene expression. In other words, even when the transcription of a gene does not differ between males and females, the epigenetic underpinnings of that expression may differ. Finally, recent evidence suggests that sex differences in epigenetic marks may primarily serve to make gene expression more similar in males and females. We discuss the implications of these findings for understanding sex differences in susceptibility to disease, and point to recent conceptual and technical advances likely to influence the field going forward.