Early-life undernutrition induces enhancer RNA remodeling in mice liver

Abstract

Background 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. Results 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. Conclusions 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.

Amplifying gene expression with RNA-targeted therapeutics

“…Notably, expression patterns of these RNAs are known to be tissue specific, which makes them attractive as potential therapeutic targets 114 . Expression of eRNAs is also stimulus specific; for instance, particular subsets of eRNAs are preferentially expressed at inflammation-related genes in response to inflammatory stimuli, in neurons during the stimulus-induced expression of immediate early genes and after exposure to early-life undernutrition 115 – 117 . An experience-induced enhancer lncRNA, ADRAM (activity-dependent lncRNA associated with memory), is generated by an enhancer of Nr4a2 (nuclear receptor subfamily 4, group A, member 2).…”

Natural antisense transcripts as drug targets

“…For instance, eRNAs are preferentially expressed at inflammation-related genes in response to inflammatory stimuli (Wan et al, 2022). Global run-on sequencing (GRO-seq) has demonstrated that expression of eRNA is altered in response to early-life undernutrition (Wang Y. et al, 2021). In neurons, eRNAs are expressed at immediate early genes after stimulus.…”