Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility

Abstract

There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders.

Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus

“…Xist is responsible for transcriptional silencing of one of the two X chromosomes to equalize the dosage of X-linked genes between the sexes (X-chromosome inactivation). Skewed X-chromosome inactivation has been implicated in a variety of X-linked neurological diseases and mental illness, such as developmental delay and autism-predisposing chromosomal aberration (Migeon 2006; Qureshi and Mehler 2010; Willard 1996). …”

Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice

“…Sexual differentiation has long been considered “epigenetic,” in reference to the indirect role that sex chromosomes play in hormone-dependent sex differences. More recently, the term “epigenetics” has re-entered the sexual differentiation field, but now to refer much more specifically to changes in chromatin that lead to long-term changes in gene expression without any change in the underlying DNA sequence (McCarthy et al, 2009b; Qureshi and Mehler, 2010; Auger and Auger, 2011; Xu and Andreassi, 2011). …”

Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

“…However, the observed effects and their gender specificity (across two species) are intriguing. While we currently have no mechanistic insight into this gender specificity, part of the explanation may lie in the fact that Baiap3 is expressed in sexually dimorphic brain regions such as the hypothalamus, amygdala and the bed nucleus of the stria terminalis (38,39).…”