Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
EBioMedicine. 2017 May;19:60-72. doi: 10.1016/j.ebiom.2017.03.037. Epub 2017 Apr 26.
Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.
实验研究表明，早期生活环境通过表观遗传过程对肥胖风险有很大的影响。我们研究了与儿童肥胖相关的人类出生组织中个体间 DNA 甲基化差异。我们在长链非编码 RNA ANRIL（编码于 CDKN2A 基因）的启动子内发现了一个新的与出生时 CpG 甲基化水平与儿童 6 岁时肥胖相关的关联。在来自不同种族的新生儿的出生组织、青少年外周血和成人脂肪组织中也观察到了 ANRIL 甲基化与肥胖之间的关联。此外，CpG 甲基化与体内 ANRIL 表达相关，体外 CpG 诱变抑制了 ANRIL 启动子活性。此外，CpG 甲基化增强了与 ANRIL 启动子内雌激素反应元件的结合。我们的研究结果表明，与基因功能相关的围产期甲基化可能是肥胖的一个强有力的标志物，为早期生活环境对人类健康的长期影响的表观遗传过程提供了有力的支持。
