Early-life undernutrition induces enhancer RNA remodeling in mice liver

Epigenetics & Chromatin

Xianfu Yi¹  Jianzhong Sheng²  Yinyu Wang³  Yiran Zhao³  Yiting Mao³  Guolian Ding⁴  Xinmei Liu⁴  Yicong Meng⁴  Hefeng Huang⁴  Chuanjin Yu⁴ 

[1] School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China;Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China;Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China;The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China;Institute of Embryo-Fetal Original Adult Disease Affiliated To Shanghai, Jiao Tong University School of Medicine, Shanghai, China;

关键词: Early-life undernutrition;    Global run-on sequencing;    Nascent RNA;    Enhancer;    Metabolism;   

DOI  :  10.1186/s13072-021-00392-w

来源: Springer

【 摘 要 】

BackgroundMaternal 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.ResultsUsing 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.ConclusionsOur 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.

【 授权许可】

CC BY