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首页> 外文期刊>Environmental Epigenetics >Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets
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Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets

机译：产后早期营养过剩会加速胰岛衰老相关的表观遗传漂移

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Pancreatic islets of type 2 diabetes patients have altered DNA methylation, contributing to islet dysfunction and the onset of type 2 diabetes. The cause of these epigenetic alterations is largely unknown. We set out to test whether (i) islet DNA methylation would change with aging and (ii) early postnatal overnutrition would persistently alter DNA methylation. We performed genome-scale DNA methylation profiling in islets from postnatally over-nourished (suckled in a small litter) and control male mice at both postnatal day 21 and postnatal day 180. DNA methylation differences were validated using quantitative bisulfite pyrosequencing, and associations with expression were assessed by RT-PCR. We discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging ( R sup2/sup = 0.33, P ?0.0001). These methylation differences were inversely correlated with mRNA expression of genes relevant to β cell function [including Rab3b (Ras-related protein Rab-3B), Cacnb3 (voltage-dependent L-type calcium channel subunit 3), Atp2a3 (sarcoplasmic/endoplasmic reticulum calcium ATPase 3) and Ins2 (insulin 2)]. Relative to control, small litter islets showed DNA methylation differences directly after weaning and in adulthood, but few of these were present at both ages. Surprisingly, we found substantial overlap of methylated loci caused by aging and small litter feeding, suggesting that the age-associated gain of DNA methylation happened much earlier in small litter islets than control islets. Our results provide the novel insights that aging-associated DNA methylation increases reflect an epigenetic drift toward the exocrine pancreas epigenome, and that early postnatal overnutrition may accelerate this process.
机译：2型糖尿病患者的胰岛DNA甲基化改变，导致胰岛功能障碍和2型糖尿病的发作。这些表观遗传改变的原因在很大程度上是未知的。我们着手测试（i）胰岛DNA甲基化是否会随着年龄的增长而发生变化，以及（ii）产后早期营养过剩会持续改变DNA甲基化。我们在出生后第21天和出生后第180天，对来自营养过剩的婴儿（吸入小垫子）和对照雄性小鼠的胰岛进行了基因组规模的DNA甲基化分析。使用定量的亚硫酸氢盐焦磷酸测序法验证了DNA甲基化差异，并与表达相关通过RT-PCR评估。我们发现外分泌相对于内分泌胰腺而言甲基化程度较高的基因组区域在衰老过程中会在胰岛中获得甲基化作用（R 2 = 0.33，P <？0.0001）。这些甲基化差异与与β细胞功能相关的基因的mRNA表达呈负相关[包括Rab3b（Ras相关蛋白Rab-3B），Cacnb3（电压依赖性L型钙通道亚基3），Atp2a3（肌浆/内质网钙） ATPase 3）和Ins2（胰岛素2）]。相对于对照，小仔猪断奶后和成年后直接表现出DNA甲基化差异，但是在两个年龄段都很少。出乎意料的是，我们发现由衰老和小窝饲喂引起的甲基化基因座大量重叠，这表明与小岛胰岛相比，与年龄相关的DNA甲基化发生得早于对照小岛。我们的结果提供了新的见解，即衰老相关的DNA甲基化增加反映了表观遗传向外分泌胰腺表观基因组的漂移，而出生后早期的营养过剩可能会加速这一过程。

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