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

Blencowe, Montgomery; Itoh, Yuichiro; Chen, Xuqi; Zhao, Yutian; Han, Yanjie; Shou, Benjamin L.; McClusky, Rebecca; Reue, Karen; Arnold, Arthur P.; Yang, Xia

doi:10.1101/2021.07.18.451543

Cited by 6 publications

(10 citation statements)

References 59 publications

(105 reference statements)

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“…We focused on liver because of its central role in regulating homeostatic lipid levels and as the primary target for statin inhibition of cholesterol synthesis. Previous studies have identified significant sex differences in the hepatic transcriptome [26][27][28]. Our study extends and augments previous work by assessing the role of sex in hepatic gene regulation in physiological states that are relevant to human disease-hypercholesterolemia and statin treatment.…”

Section: Discussionsupporting

confidence: 69%

Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment

Wiese

Agle

Zhang

et al. 2022

Preprint

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Background: Biological sex impacts susceptibility and presentation of cardiovascular disease, which remains the leading cause of death for both sexes. To reduce cardiovascular disease risk, statin drugs are commonly prescribed to reduce circulating cholesterol levels through inhibition of cholesterol synthesis. The effectiveness of statin therapy differs between individuals with a sex bias in the frequency of adverse effects. Limited information is available regarding the mechanisms driving sex-specific responses to hypercholesterolemia or statin treatment. Methods: Four core genotypes mice (XX and XY mice with ovaries and XX and XY mice with testes) on a hypercholesteremic Apoe—/— background were fed a chow diet without or with simvastatin for 8 weeks. Plasma lipid levels were quantified and hepatic differential gene expression was evaluated with RNA-sequencing to identify the independent effects of gonadal and chromosomal sex. Results: In a hypercholesterolemic state, gonadal sex influenced the expression levels of more than 3000 genes, and chromosomal sex impacted expression of nearly 1400 genes, which were distributed across all autosomes as well as the sex chromosomes. Gonadal sex uniquely influenced the expression of ER stress response genes, whereas chromosomal and gonadal sex influenced fatty acid metabolism gene expression in hypercholesterolemic mice. Sex–specific effects on gene regulation in response to statin treatment included a compensatory upregulation of cholesterol biosynthetic gene expression on mice with XY chromosome complement, regardless of presence of ovaries or testes.

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Section: Discussionsupporting

confidence: 69%

Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment

Wiese

Agle

Zhang

et al. 2022

Preprint

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“…In female cells, biological processes belonging to cell organization and cell compartment are delayed, while in male cells, RNA and DNA related processes are delayed. Overall, our results reveal the emergence of early-acting sexual networks among males and females, thus, placing prominence on the role of sex chromosomes during early stages of organismal development 34,35 .…”

Section: Discussionmentioning

confidence: 67%

Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals

Richardson

Zhange

Engel

et al. 2022

Preprint

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Mammalian gonadal sex is determined by the presence or absence of a Y chromosome. In males, the Y chromosome initiates male gonadogenesis and the subsequent production of male-specific hormones defines the male state of each cell in the organism. In females, the lack of a Y chromosome and the presence of two X chromosomes triggers the development of female gonads, hormones, and cellular identity. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression. Here we apply a comparative bioinformatic analysis on published single-cell datasets in mouse and human during very early embryogenesis - from two-cell to preimplantation stages - to characterize sex-specific signals and to assess the degree of conservation among early acting sex-specific genes and pathways. Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis. In addition, gene expression signals from male and female gametes during fertilization may still be present. Although these transcriptional sex effects rapidly diminish, the sex-biased expression of epigenetic enzymes has the potential to establish sex-specific patterns that persist beyond implantation. Sex-biased genes appear to form sex-specific protein-protein interaction networks across preimplantation stages in both mammals. While the distribution of sex-differentially expressed genes (sexDEGs) in early embryonic stages are similar in mice and humans, the genes involved are generally different. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages including post-fertilization, epigenetic, and preimplantation ontologies conserved between mouse and human. This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.

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“…Because of the comparisons we had the capacity to make here, we cannot fully distinguish the relative importance of sex chromosomes, sex hormones and gonadal sex on driving sex differences in gene expression in the samples studied here. Recent work in adult tissues (liver and adipose) in a mouse model reports the strongest effect of activational hormones, followed by a lesser organizational gonad effect, with a third strongest role of sex chromosome complement on sex differences in gene expression (Blencowe et al, 2022). Thus, one can hypothesize that a similar hierarchy may be in place for shaping sex differences in gene expression in humans.…”

Section: Perspectives and Significancementioning

confidence: 99%

“…Further, a recent study of adult tissues from the Genotype-Tissue Expression Project (GTEx) demonstrated that sex influences gene expression and cellular composition throughout the body with 37% of all genes showing sex differences in expression in at least one tissue (Oliva et al, 2020). In mouse, chromosomal sex contributes, along with organizational gonadal sex and activational hormones, to sex differences in gene expression in adult tissues (Blencowe et al, 2022) in adult tissues. However, sex differences in early formed placental tissues have not been compared with sex differences in adult tissues.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in early and term placenta are conserved in adult tissues

Olney

Plaisier

Phung

et al. 2022

Preprint

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Background: Pregnancy complications vary based on the fetus's genetic sex, which may, in part, be modulated by the placenta. Further, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different time points throughout pregnancy and comparisons to adult tissues remains poorly characterized. Methods: Here, we collect and characterize sex differences in gene expression in term placentas (≥ 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx. Results: We identify 268 and 53 sex differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex differentially expressed genes observed in the term placentas, 31 are also sex differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males. Conclusions: We find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes.

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

Cited by 6 publications

References 59 publications

Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment

Chromosomal and gonadal sex drive sex differences in lipids and hepatic gene expression in response to hypercholesterolemia and statin treatment

Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals

Sex differences in early and term placenta are conserved in adult tissues

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