Alexander Jacqueline, Teague April M, Chen Jing, Aston Christopher E, Leung Yuet-Kin, Chernausek Steven, Simmons Rebecca A, Pinney Sara E
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Department of Pediatrics, CMRI Metabolic Research Program, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
PLoS One. 2018 Feb 22;13(2):e0190698. doi: 10.1371/journal.pone.0190698. eCollection 2018.
AIMS/HYPOTHESIS: We hypothesized that diabetes during pregnancy (DDP) alters genome-wide DNA methylation in placenta resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression.
We mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Bead Chip in term fetal placentae from Native American and Hispanic women with DDP using a nested case-control design (n = 17 pairs). RNA expression and protein levels were assayed via RNA-Seq and Western Blot.
Genome-wide DNA methylation analysis revealed 465 CpG sites with significant changes for male offspring, 247 for female offspring, and 277 for offspring of both sexes (p<0.001). Placentae from female offspring were 40% more likely to have significant gains in DNA methylation compared with placentae from male offspring exposed to DDP (p<0.001). Changes in DNA methylation corresponded to changes in RNA and protein levels for 6 genes: PIWIL3, CYBA, GSTM1, GSTM5, KCNE1 and NXN. Differential DNA methylation was detected at loci related to mitochondrial function, DNA repair, inflammation, oxidative stress.
CONCLUSIONS/INTERPRETATION: These findings begin to explain mechanisms responsible for the increased risk for obesity and type 2 diabetes in offspring of mothers with DDP.
目的/假设：我们推测孕期糖尿病（DDP）会改变胎盘全基因组的DNA甲基化，导致代谢相关基因的甲基化位点差异以及RNA和蛋白质表达的下游变化。
我们采用巢式病例对照设计（n = 17对），使用Infinium 450K人类甲基化芯片对患有DDP的美国原住民和西班牙裔女性足月胎儿胎盘进行全基因组DNA甲基化图谱绘制。通过RNA测序和蛋白质印迹法检测RNA表达和蛋白质水平。
全基因组DNA甲基化分析显示，男性后代有465个CpG位点发生显著变化，女性后代有247个，两性后代有277个（p<0.001）。与暴露于DDP的男性后代胎盘相比，女性后代胎盘DNA甲基化显著增加的可能性高40%（p<0.001）。DNA甲基化的变化与6个基因（PIWIL3、CYBA、GSTM1、GSTM5、KCNE1和NXN）的RNA和蛋白质水平变化相对应。在与线粒体功能、DNA修复、炎症、氧化应激相关的位点检测到DNA甲基化差异。
结论/解读：这些发现开始解释患有DDP的母亲的后代肥胖和2型糖尿病风险增加的机制。
