Transcriptomic signatures of menopause across human tissues

摘要 更年期是女性衰老的一个重要里程碑。不幸的是，绝经后的女性 绝经后的冠心病、中风和死亡风险。这可以部分归因于增长 在心血管疾病(CVD)方面，许多女性在绝经后经历的危险因素，如血液 压力、血脂水平和肥胖，但这些变化和其他变化背后的机制还知之甚少。 血液中雌激素水平的降低是更年期的主要变化之一，而雌激素可以 转录调控许多基因，通常是以组织特有的方式。基因变化的先期研究 绝经期患者的表达有限，大多数集中在乳房、骨骼和女性 生殖组织。我们假设心脏新陈代谢组织的转录检测 更年期转变将揭示导致心血管疾病风险增加的分子过程。 尽管绝经状态信息在大多数人类组织基因表达数据集中缺失，但我们 假设绝经状态可以从基因表达数据中推断出来。为实现这一目标，在目标1A中 我们将推断数百名女性基因组织表达(GTEx)受试者的绝经状态 利用维度组合对其女性生殖组织的基因表达谱进行研究 由已知生物学和更不可知的、基于集群的方法提供信息的减少方法。自.以来 GTEx受试者平均贡献了超过18个组织的样本，我们将推断出更年期状态 非生殖组织的信息也是如此。在子宫基因表达数据的初步分析中 (保留年龄作为协变量)，我们观察到明确的个体分类为推断的绝经前 (54岁)和推断的绝经后组(48岁)。由于更年期状态因年龄而变得混乱，在 目的1B我们将确定性别特异的衰老基因，并研究基因表达与 每个性别子集按时间顺序排列的年龄。在目标1C中，我们将使用从 目的1确定在推断的组织中差异表达的基因和途径。 绝经前和绝经后妇女，重点关注与以下方面相关的心脏代谢组织 心血管疾病，如肝脏、脂肪和血管。推断出与更年期相关的基因 男性组织中的年龄与实际年龄没有表现出类似的相关性，很可能是由女性- 更年期特定的荷尔蒙变化，而不是更普遍的衰老过程。总的来说，这将是 到目前为止，对更年期对基因表达影响的最全面评估，以及 这些发现可以确定绝经后妇女疾病负担增加的分子途径。

SUMMARY An important aging milestone for women is menopause. Unfortunately, postmenopausal women have increased coronary heart disease, stroke, and mortality risk after menopause. This can be partially attributed to increases in cardiovascular disease (CVD) risk factors that many women experience after menopause, such as blood pressure, lipid levels, and adiposity, but the mechanisms behind these and other changes are poorly understood. A reduction in circulating estrogen levels is one of the major changes with menopause, and estrogen can transcriptionally regulate many genes, often in a tissue-specific manner. Prior studies of changes in gene expression with menopause have been limited, and most have been focused on breast, bone, and female reproductive tissues. We hypothesize that transcriptomic examination of cardiometabolic tissues across the menopause transition will reveal insight into the molecular processes responsible for the increased CVD risk. Though menopause status information is missing from most human tissue gene expression datasets, we hypothesize that menopausal status can be inferred from gene expression data. To accomplish this, in Aim 1A we will infer the menopausal status of hundreds of female Genotype-Tisssue Expression (GTEx) subjects based on the gene expression profiles of their female reproductive tissues, using a combination of dimensionality reduction approaches informed by known biology and more agnostic, clustering-based methodology. Since the average GTEx subject contributed samples from over 18 tissues, we will have inferred menopausal status information for non-reproductive tissues as well. In a preliminary analysis of uterus gene expression data (withholding age as a covariate), we observed clear classification of individuals into an inferred premenopausal (age<54) and an inferred postmenopausal group (age>48). Since menopause status is confounded by age, in Aim 1B we will identify sex-specific aging genes and examine the relationship of gene expression with chronological age in each sex subset. In Aim 1C, we will use the inferred menopausal status information from Aim 1A to identify genes and pathways that are differentially expressed in tissues derived from inferred premenopausal versus postmenopausal women, focusing on cardiometabolic tissues of relevance to cardiovascular disease, such as liver, adipose, and blood vessels. Inferred menopause-related genes that do not exhibit similar correlations with chronological age in male tissues are likely to be regulated by the female- specific hormonal changes during menopause rather than more general aging processes. Overall, this will be the most comprehensive evaluation of the effects of menopause on gene expression performed to date, and the findings could identify molecular pathways underlying the increased disease burden in post-menopausal women.