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.

中文翻译：

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性激素、性染色体和性腺对组织基因调控性别差异的相对贡献


哺乳动物生理和疾病的性别差异是由三类因素的影响造成的，这些因素在雄性和雌性中本质上是不平等的：性腺激素的可逆（激活）效应、性腺激素的永久（组织）效应以及性腺激素的细胞自主效应。性染色体，以及由此类因素驱动的基因。通常，这些因素共同作用导致特定表型的性别差异，但每个因素的相对贡献以及它们之间的相互作用仍不清楚。在这里，我们使用有或没有激素替代的四种核心基因型（FCG）小鼠模型来区分每类性别偏见因素对肝脏和脂肪组织转录组调节的影响。我们发现激活激素水平对基因表达的影响最强，其次是组织性腺性别效应，最后是性染色体效应，以及三个因素之间的相互作用。组织特异性很突出，雌二醇对脂肪组织基因调节和睾酮对肝脏转录组有重大影响。受三种性别偏见因素影响的网络包括发育、免疫和新陈代谢，并为这些网络确定了组织特异性调节因子。此外，受个体性别偏见因素和因素之间相互作用影响的基因与人类疾病特征相关，如冠状动脉疾病、糖尿病和炎症性肠病。我们的研究提供了主要性别偏见因素对基因调控的个体和交互贡献的组织特异性解释，这些基因调控对系统代谢、内分泌和免疫功能具有广泛的影响。