Metabolic Research Laboratories, Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5449-54. doi: 10.1073/pnas.1019007108. Epub 2011 Mar 8.
Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.
环境因素在整个生命过程中与基因组相互作用，决定基因表达，进而决定组织功能和疾病风险。已知有一种因素在决定长期代谢健康方面起着重要作用，那就是在发育关键期的饮食。基因表达的表观遗传调控被认为介导了早期饮食的这种编程效应。这些影响的确切表观遗传机制在很大程度上仍然未知。在这里，我们表明，转录因子 Hnf4a 与 2 型糖尿病 (T2D) 的病因有关，它受到母代饮食和大鼠胰岛衰老的表观遗传调控。Hnf4a 在胰岛中的转录活性通过其开放染色质结构和 P2 启动子与下游增强子之间的胰岛特异性相互作用限制在远端 P2 启动子上。在早期发育过程中暴露于次优营养会导致增强子区域的表观遗传沉默，从而削弱 P2 启动子-增强子相互作用，并导致 Hnf4a 表达的永久性降低。衰老会导致胰岛中整个 Hnf4a 基因座的渐进性表观遗传沉默，在暴露于不良母代饮食的大鼠中更为明显。我们的研究结果为环境诱导的 Hnf4a 增强子表观遗传变化提供了证据，这些变化改变了它与 P2 启动子的相互作用，从而决定了 T2D 的风险。因此，我们提出，启动子-增强子相互作用的环境诱导变化代表了营养和衰老影响长期健康的一种基本表观遗传机制。
