Transcriptomic signatures of menopause across human tissues

总结 女性衰老的一个重要里程碑是更年期。不幸的是，绝经后的妇女 绝经后冠心病、中风和死亡风险。部分原因是， 在许多女性绝经后经历的心血管疾病（CVD）风险因素中，如血液 血压，血脂水平和肥胖，但这些和其他变化背后的机制知之甚少。 循环中雌激素水平的降低是更年期的主要变化之一，雌激素可以 转录调节许多基因，通常以组织特异性方式。基因变化的先前研究 绝经期的表达有限，大多数集中在乳腺、骨骼和女性 生殖组织我们假设，对心脏代谢组织进行转录组学检查， 绝经过渡期将揭示对心血管疾病风险增加负责的分子过程的洞察。 虽然大多数人类组织基因表达数据集缺少绝经状态信息，但我们 假设绝经状态可以从基因表达数据推断。为此，在目标1A中， 我们将根据基因型-组织表达（GTEx）推断数百名女性受试者的绝经状态， 在他们的女性生殖组织的基因表达谱，使用维度的组合， 减少方法由已知的生物学和更不可知的，聚类为基础的方法。以来 平均GTEx受试者提供了来自超过18种组织的样本，我们将推断绝经状态 非生殖组织的信息。在对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人分类为推断的绝经前 (age<54）和推断的绝经后组（年龄>48）。由于绝经状态受年龄的影响， 目的1B我们将鉴定性别特异性衰老基因，并研究基因表达与衰老的关系。 每个性别子集的实际年龄。在目标1C中，我们将使用从 目的1A鉴定在来自推断的组织中差异表达的基因和途径， 绝经前与绝经后女性，重点关注与以下相关的心脏代谢组织： 心血管疾病，如肝脏、脂肪和血管。推测的更年期相关基因 在男性组织中，与实足年龄没有表现出类似的相关性，很可能是由女性调节的- 更年期的荷尔蒙变化，而不是更普遍的衰老过程。总的来说，这将是 迄今为止，对绝经对基因表达影响的最全面评估， 研究结果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.