Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort
Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort
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DOI：
10.1080/15592294.2018.1497387
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发表时间：
2018-01-01
期刊：
影响因子：
3.7
通讯作者：
Wright, Rosalind J.
中科院分区：
文献类型：
--
作者：
Brunst, Kelly J.;Tignor, Nicole;Wright, Rosalind J.
不断变化的证据将母体压力暴露与调节胎盘功能的特定基因的胎盘 DNA 甲基化的变化联系起来，这可能对许多慢性疾病的编程产生影响。很少有研究采用全表观基因组方法。使用 Infinium HumanMmethylation450 BeadChip (450K)，我们研究了表观基因组范围的胎盘 DNA 甲基化与母亲一生中遭受创伤性和非创伤性压力源的经历之间的关系，并使用生活压力源清单修订版 (LSC-R) 调查 (n=207) 进行评估。我们发现 112 个 CpG 的 DNA 甲基化差异具有表观基因组范围内的统计显着性 (FDR=0.05)。此外，我们观察到三个簇表现出差异甲基化以应对母亲一生的高压力。在 FDR=0.20 下进行的富集分析表明，赖氨酸降解是与母亲一生压力暴露相关的最重要途径。使用间隙统计鉴定的三个最大探针簇的靶向富集分析富集了与内吞作用（即 SMAP1、ANKFY1）、紧密连接（即 EPB41L4B）和代谢途径（即 INPP5E、EEF1B2）相关的基因。这些途径也在与母亲一生压力暴露相关的前 10 条 KEGG 途径中被确定，在胎儿正常发育所需的多种生理功能中发挥着重要作用。此外，还鉴定出两个基因表现出与母亲一生压力相关的多个探针（即 ANKFY1、TM6SF1）。属于每个簇的探针的甲基化状态和/或表现出多次命中的基因，可能在终生压力暴露增加的母亲所生的孩子的不良健康结果的发病机制中发挥作用。
Evolving evidence links maternal stress exposure to changes in placental DNA methylation of specific genes regulating placental function that may have implications for the programming of a host of chronic disorders. Few studies have implemented an epigenome-wide approach. Using the Infinium HumanMethylation450 BeadChip (450K), we investigated epigenome-wide placental DNA methylation in relation to maternal experiences of traumatic and non-traumatic stressors over her lifetime assessed using the Life Stressor Checklist-Revised (LSC-R) survey (n=207). We found differential DNA methylation at epigenome-wide statistical significance (FDR=0.05) for 112 CpGs. Additionally, we observed three clusters that exhibited differential methylation in response to high maternal lifetime stress. Enrichment analyses, conducted at an FDR=0.20, revealed lysine degradation to be the most significant pathway associated with maternal lifetimes stress exposure. Targeted enrichment analyses of the three largest clusters of probes, identified using the gap statistic, were enriched for genes associated with endocytosis (i.e., SMAP1, ANKFY1), tight junctions (i.e., EPB41L4B), and metabolic pathways (i.e., INPP5E, EEF1B2). These pathways, also identified in the top 10 KEGG pathways associated with maternal lifetime stress exposure, play important roles in multiple physiological functions necessary for proper fetal development. Further, two genes were identified to exhibit multiple probes associated with maternal lifetime stress (i.e., ANKFY1, TM6SF1). The methylation status of the probes belonging to each cluster and/or genes exhibiting multiple hits, may play a role in the pathogenesis of adverse health outcomes in children born to mothers with increased lifetime stress exposure.