Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation
- Montgomery Blencowe1,2,
- Xuqi Chen1,3,
- Yutian Zhao1,2,
- Yuichiro Itoh1,3,4,
- Caden N. McQuillen1,
- Yanjie Han1,
- Benjamin L. Shou1,
- Rebecca McClusky1,3,
- Karen Reue5,
- Arthur P. Arnold1,2,3 and
- Xia Yang1,2,5,6,7
- 1Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA;
- 2Interdepartmental Program of Molecular, Cellular and Integrative Physiology, University of California, Los Angeles, California 90095, USA;
- 3Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, California 90095, USA;
- 4Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
- 5Department of Human Genetics and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA;
- 6Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California 90095, USA;
- 7Molecular Biology Institute, University of California, Los Angeles, California 90095, USA
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 last, 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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275965.121.
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Freely available online through the Genome Research Open Access option.
- Received July 7, 2021.
- Accepted March 29, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
