Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria

Abstract

Several autoimmune and neurological diseases exhibit a sex bias, but discerning the causes and mechanisms of these biases has been challenging. Sex differences begin to manifest themselves in early embryonic development, and gonadal differentiation further bifurcates the male and female phenotypes. Even at this early stage, however, there is evidence that males and females respond to environmental stimuli differently, and the divergent phenotypic responses may have consequences later in life. The effect of prenatal nutrient restriction illustrates this point, as adult women exposed to prenatal restrictions exhibited increased risk factors of cardiovascular disease, while men exposed to the same condition did not. Recent research has examined the roles of sex-specific genes, hormones, chromosomes, and the interactions among them in mediating sex-biased phenotypes. Such research has identified testosterone, for example, as a possible protective agent against autoimmune disorders and an XX chromosome complement as a susceptibility factor in murine models of lupus and multiple sclerosis. Sex-biased chromatin is an additional and likely important component. Research suggesting a role for X and Y chromosome heterochromatin in regulating epigenetic states of autosomes has highlighted unorthodox mechanisms of gene regulation. The crosstalk between the Y chromosomes and autosomes may be further mediated by the mitochondria. The organelles have solely maternal transmission and exert differential effects on males and females. Altogether, research supports the notion that the interaction between sex-biased elements might exert novel regulatory functions in the genome and contribute to sex-specific susceptibilities to autoimmune and neurological diseases.

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection

“…The long arm of murine ChrY encodes several multicopy gene families, which exhibit significant strain-specific copy number variation (CNV), and the physiological roles of which are only beginning to be understood (20,21). Importantly, our studies in EAE and CVB3-induced autoimmune myocarditis revealed a strong association between CNV in multicopy ChrY genes and susceptibility to these autoimmune diseases (27,46).…”

“…Importantly, these data suggest that nonendocrine cell-intrinsic (genetic) sex-specific factors may contribute to disease susceptibility in males. In this regard, the concept that genes on the X and Y chromosomes (ChrX and ChrY) may influence sex differences is being increasingly recognized (18)(19)(20)(21), and it was recently suggested that the widely expressed ancestral singlecopy ChrY genes may function as dosage-sensitive regulators of gene expression, translation, and protein stability, and as such may play essential roles in male viability, development, and sex differences in health and disease (22).…”

Impact of prenatal polycyclic aromatic hydrocarbon exposure on behavior, cortical gene expression, and DNA methylation of the Bdnf gene

“…While the basis for this sex difference is unclear, it is consistent with recent findings that exposure to the persistent organic pollutant polychlorinated biphenyls (PCB) decreased Bdnf (but not Grin2b ) protein levels and Bdnf -mediated signaling in the adult male rat cerebral cortex [43]. We previously observed a male-specific effect of prenatal BPA exposure on reductions in hippocampal Bdnf and Grin2b gene expression and cognitive performance, and these sexspecific effects were likely the typical response to prenatal adversity [20] and may have been mediated by chromosomal, hormonal and epigenetic differences between males and females during fetal development [44–46]. …”

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

“…Moreover, mitochondrial function varies in adult males and females but the origin of these differences is unknown. [116,117] Acknowledging these gaps should lend strong impetus for bridging them with detailed, mechanistic studies.…”