Prenatal Growth Patterns and Birthweight Are Associated With Differential DNA Methylation and Gene Expression of Cardiometabolic Risk Genes in Human Placentas: A Discovery-Based Approach
Prenatal Growth Patterns and Birthweight Are Associated With Differential DNA Methylation and Gene Expression of Cardiometabolic Risk Genes in Human Placentas: A Discovery-Based Approach
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DOI：
10.1177/1933719117716779
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发表时间：
2018-04-01
影响因子：
2.9
通讯作者：
Devaskar, Sherin U.
中科院分区：
文献类型：
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作者：
Chen, Pao-Yang;Chu, Alison;Devaskar, Sherin U.
先天遗传编程和环境因素影响胎儿在子宫内的生长。生长改变胎儿的流行病学数据，无论是宫内生长受限（IUGR）或大于胎龄儿（LGA），表明这些新生儿在成年后患心脏代谢疾病的风险增加。越来越多的证据表明，子宫内的环境会导致表观遗传修饰，最终导致患心脏病或糖尿病的风险。在这项研究中，我们使用还原型亚硫酸氢盐测序来检查来自IUGR、LGA和适合胎龄（阿加）出生的后代的胎盘样本中的全基因组DNA甲基化变异，并鉴定对赋予心脏代谢疾病风险重要的基因的差异甲基化。我们发现IUGR、LGA和阿加组有不同的甲基化特征，并在这些组比较中鉴定了500多个差异甲基化基因（DMG）。功能和基因网络分析揭示了DMG与胎盘生理学和转运的预期关系，但也确定了具有生物相容性和对心脏代谢疾病具有潜在临床意义的新途径。感兴趣的DMG的特定位点的甲基化模式，与人体测量的介绍。我们进一步验证了这些特定DMG的改变的基因表达，这些特定DMG有助于血管和代谢疾病（SLC36A1，PTPRN2，CASZ 1，IL10），从而建立转录效应，以分配功能意义。我们的研究结果表明，人类胎盘的基因表达和甲基化状态与宫内环境相关且敏感，因为它影响胎儿的生长模式。我们推测这些观察到的变化可能会影响后代患成人心脏代谢疾病的风险。
Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth- altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome- wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1, IL10), thereby establishing transcriptional effects toward assigning functional significance. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment, as it affects fetal growth patterns. We speculate that these observed changes may affect risk for offspring in developing adult cardiometabolic disease.