Past, present and future of epigenetics in brain sexual differentiation

Abstract

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, hormonedependent 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. K E Y W O R D Sbrain, DNA methylation, epigenetic, histone, sex difference

Sex differences and the neurobiology of affective disorders

“…For example, in the Syrian hamster, sex steroids secreted during puberty regulate levels of spinophilin, synaptophysin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and synaptic pruning of the medial amygdala and thereby influence social and mating behaviors [79]. In rodents, during embryonic and early postnatal development, estradiol and testosterone permanently masculinize several behaviorally relevant brain structures (e.g., bed nucleus of the stria terminalis (BNST) and medial preoptic area (POA)) through modulation of the enzymes regulating epigenesis (e.g., DNA methyltransferase) [80,81]. Indeed, masculinization of both the POA and BNST (and its behavioral consequences) can be prevented by administering histone deacetylase (HDAC) inhibitors [81][82][83].…”

The neurogenetics of sexually dimorphic behaviors from a postdevelopmental perspective

“…This program, in turn, supports sex-specific cellular functions via sex-biased transcriptional and physiological states. [27][28][29][30][31][32][33][34] Because of their genetic tractability, the neuronal sexdetermination pathways of the fruit fly Drosophila melanogaster and the lab mouse Mus musculus are particularly well described. Both species produce sexually dimorphic male and female forms, which exhibit multiple sex-dependent morphological, neuroanatomical and behavioral traits.…”

New perspectives for the action of steroids in the brain

“…The special issue opens with a review on the epigenetic and nonepigenetic mechanisms that drive the sexual differentiation of the brain. 9 In particular, the mechanisms involving both histone acetylation and DNA methylation in the development of sex differences in the brain and behaviour of rodents are discussed, as well as the demonstration that sex differences in the number of neurones of a particular phenotype may be programmed by differences in DNA methylation early in life. The subsequent review discusses improvements in the study of the effects of steroids in the brain by the potential use of human induced pluripotent stem cells to develop organoids (3D neuronal cultures) for testing steroid properties and their therapeutic value.…”

“…The special issue opens with a review on the epigenetic and non‐epigenetic mechanisms that drive the sexual differentiation of the brain . In particular, the mechanisms involving both histone acetylation and DNA methylation in the development of sex differences in the brain and behaviour of rodents are discussed, as well as the demonstration that sex differences in the number of neurones of a particular phenotype may be programmed by differences in DNA methylation early in life.…”