Factors underlying variable DNA methylation in a human community cohort
Factors underlying variable DNA methylation in a human community cohort
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DOI：
10.1073/pnas.1121249109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Kobor, Michael S.
中科院分区：
文献类型：
--
作者：
Lam, Lucia L.;Emberly, Eldon;Kobor, Michael S.
表观遗传学正在成为解释早期生活经历的持续基因组嵌入的一种有吸引力的机制。表观遗传标记与染色质紧密相连，染色质将DNA包装成染色体，主要用于调节基因的活性。DNA甲基化是构成表观基因组的许多染色质标记中最容易获得和表征的组成部分，使其成为人类群体表观遗传学研究的理想目标。在这里，使用从社区为基础的早期社会经济地位分层的队列中收集的外周血单个核细胞，我们测量了超过14,000个人类基因启动子区域的DNA甲基化。利用这种方法，我们广泛地评估和表征了表观遗传变异，确定了塑造表观基因组的一些因素，并确定了其与基因表达的功能关系。我们发现外周血的白细胞组成与许多位点的DNA甲基化模式共同变化，人口统计学因素（如性别、年龄和种族）也是如此。此外，心理社会因素，如感知压力和皮质醇输出与DNA甲基化有关，早期社会经济地位也与DNA甲基化有关。有趣的是，我们确定DNA甲基化与外周血单个核细胞对参与toll样受体的微生物产物刺激的体外炎症反应密切相关。相比之下，我们的工作发现DNA甲基化标记对个体间相关基因表达的影响有限，这表明两者之间的关系比预期的要复杂得多。
Epigenetics is emerging as an attractive mechanism to explain the persistent genomic embedding of early-life experiences. Tightly linked to chromatin, which packages DNA into chromosomes, epigenetic marks primarily serve to regulate the activity of genes. DNA methylation is the most accessible and characterized component of the many chromatin marks that constitute the epigenome, making it an ideal target for epigenetic studies in human populations. Here, using peripheral blood mononuclear cells collected from a community-based cohort stratified for early-life socioeconomic status, we measured DNA methylation in the promoter regions of more than 14,000 human genes. Using this approach, we broadly assessed and characterized epigenetic variation, identified some of the factors that sculpt the epigenome, and determined its functional relation to gene expression. We found that the leukocyte composition of peripheral blood covaried with patterns of DNA methylation at many sites, as did demographic factors, such as sex, age, and ethnicity. Furthermore, psychosocial factors, such as perceived stress, and cortisol output were associated with DNA methylation, as was early-life socioeconomic status. Interestingly, we determined that DNA methylation was strongly correlated to the ex vivo inflammatory response of peripheral blood mononuclear cells to stimulation with microbial products that engage Toll-like receptors. In contrast, our work found limited effects of DNA methylation marks on the expression of associated genes across individuals, suggesting a more complex relationship than anticipated.