Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation

Abstract

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the Four Core Genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect and, lastly, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation, and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions.

Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes

“…However, the effects of the physical or sociocultural environment, nutrition, or stress (that is, the effects of gender) were not always excluded in these reports. Only a few studies describing the effects of sex steroids, such as oestradiol and testosterone, on gene regulation in adipose tissue, the liver transcriptome and gene networks associated with metabolic, immune and vascular regulation have overcome this limitation by excluding environmental effects 22 . The affected genes were associated with human disease traits such as CAD, diabetes mellitus and inflammatory bowel disease, suggesting that these disease traits arise as a result of biological mechanisms.…”

Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain

“…Therefore, considering the particular nature of sex chromosomes and their inheritance, it is possible to identify at least five mechanisms potentially involved in the establishment of sex differences independently of the action of gonadal hormones ( Figure 2 ): (1) expression of MSY-linked genes (only present in XY individuals), (2) increased expression in XX individuals of X-linked genes escaping XCI, (3) reduced expression of PARs-linked genes in XX individuals due to XCI, (4) differences in X gene expression due to genomic imprinting and (5) sequestration of transcriptional regulators such as heterochromatin assembly factors and other epigenetic modifiers for Xi silencing in XX individuals, which would limit the availability of such factors for regulation of autosomal gene expression [ 15 , 58 , 81 , 87 , 88 ]. Delving into these differentiation mechanisms is contributing to the final understanding of sex chromosome dosage effects on genome-wide autosomal expression, which are already known to span a diversity of cellular functions such as cell fate, cell-cycle regulation, chromatin organization, immune response signaling, protein trafficking and energy metabolism [ 58 , 65 , 89 , 90 , 91 ].…”

The X factor in neurodegeneration

“…Elegant studies have established how to disentangle the effect of XX versus XY sex chromosome complement from the effect of gonadal type (sex hormones; Smith-Bouvier et al, 2008 ) using the Four Core Genotype (FCG) mice ( Arnold, 2004 ; Arnold and Burgoyne, 2004 ). This model has been used worldwide to study sex differences in health (development and adulthood) and diseases (autoimmunity, cardiovascular, and metabolic, to name a few; Blencowe et al, 2022 ). The Y chromosome gene that encodes for testicular development ( sex determining region Y , Sry ) is deleted, with mice designated XY−, and they are ovary-bearing (gonadal females).…”