Chen Pao-Yang, Chu Alison, Liao Wen-Wei, Rubbi Liudmilla, Janzen Carla, Hsu Fei-Man, Thamotharan Shanthie, Ganguly Amit, Lam Larry, Montoya Dennis, Pellegrini Matteo, Devaskar Sherin U
1 Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan.
2 Division of Neonatology and Developmental Biology, Department of Pediatrics, Neonatal Research Center of the UCLA Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Reprod Sci. 2018 Apr;25(4):523-539. doi: 10.1177/1933719117716779. Epub 2017 Jul 11.
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.
内在的基因编程和环境因素会影响子宫内胎儿的生长。生长改变的胎儿，即宫内生长受限（IUGR）或大于胎龄（LGA）的流行病学数据表明，这些新生儿成年后患心脏代谢疾病的风险增加。越来越多的证据表明，子宫内环境会导致表观遗传修饰，从而增加最终患心脏病或糖尿病的风险。在本研究中，我们使用简化代表性亚硫酸氢盐测序来检查来自IUGR、LGA和适于胎龄（AGA）出生后代的胎盘样本中的全基因组DNA甲基化变异，并确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AGA组有明显的甲基化特征，并在这些组比较中鉴定出500多个差异甲基化基因（DMG）。功能和基因网络分析揭示了DMG与胎盘生理和转运的预期关系，但也确定了对心脏代谢疾病具有生物学合理性和潜在临床重要性的新途径。感兴趣的DMG的特定位点具有与人体测量表现密切相关的甲基化模式。我们进一步验证了这些特定DMG的基因表达改变与血管和代谢疾病（SLC36A1、PTPRN2、CASZ1、IL10）有关，从而确立了赋予功能意义的转录效应。我们的结果表明，人类胎盘的基因表达和甲基化状态与子宫内环境相关且对其敏感，因为它会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。
