Maternal protein restriction diet (PRD) increases the risk of metabolic dysfunction in adulthood, the mechanisms during the early life of offspring are still poorly understood. Apart from genetic factors, epigenetic mechanisms are crucial to offer phenotypic plasticity in response to environmental situations and transmission. Enhancer-associated noncoding RNAs (eRNAs) transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription. Using global run-on sequencing (GRO-seq) of nascent RNA including eRNA and total RNA sequencing data, we show that early-life undernutrition causes remodeling of enhancer activity in mouse liver. Differentially expressed nascent active genes were enriched in metabolic pathways. Besides, our work detected a large number of high confidence enhancers based on eRNA transcription at the ages of 4 weeks and 7 weeks, respectively. Importantly, except for ~ 1000 remodeling enhancers, the early-life undernutrition induced instability of enhancer activity which decreased in 4 weeks and increased in adulthood. eRNA transcription mainly contributes to the regulation of some important metabolic enzymes, suggesting a link between metabolic dysfunction and enhancer transcriptional control. We discovered a novel eRNA that is positively correlated to the expression of circadian gene Cry1 with increased binding of epigenetic cofactor p300. Our study reveals novel insights into mechanisms of metabolic dysfunction. Enhancer activity in early life acts on metabolism-associated genes, leading to the increased susceptibility of metabolic disorders.

中文翻译：

---

生命早期营养不良诱导小鼠肝脏增强子 RNA 重塑

母体蛋白质限制饮食 (PRD) 会增加成年期代谢功能障碍的风险，但对后代早期生命中的机制仍知之甚少。除了遗传因素外，表观遗传机制对于提供表型可塑性以响应环境情况和传播至关重要。增强子相关的非编码 RNA (eRNA) 转录作为增强子激活的有力指标，在介导增强子功能和基因转录方面具有潜在作用。使用包括 eRNA 和总 RNA 测序数据在内的新生 RNA 的全局连续测序 (GRO-seq)，我们表明早期营养不良会导致小鼠肝脏中增强子活性的重塑。差异表达的新生活性基因在代谢途径中富集。除了，我们的工作分别在 4 周和 7 周时检测到大量基于 eRNA 转录的高置信度增强子。重要的是，除了约 1000 种重塑增强剂外，早期营养不良会导致增强剂活性不稳定，这种不稳定会在 4 周内下降并在成年期增加。eRNA 转录主要有助于调节一些重要的代谢酶，表明代谢功能障碍与增强子转录控制之间存在联系。我们发现了一种新的 eRNA，它与昼夜节律基因 Cry1 的表达呈正相关，并增加了表观遗传辅因子 p300 的结合。我们的研究揭示了对代谢功能障碍机制的新见解。生命早期的增强活性作用于代谢相关基因，导致代谢紊乱的易感性增加。