Abstract
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.
Highlights
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
Activated transcription is controlled by activators located in both the promoter-proximal site and distal regulatory site [14], which results in the transcription of enhancer-associated noncoding RNAs [16]
ERNA transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription [20,21,22], which can be applied to understanding the transcriptional regulation of disease, like tumorigenesis [23, 24]
Summary
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. 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. Metabolic syndrome is defined as a combination of central obesity and insulin resistance (IR) with impairment of glucose, blood pressure or lipid metabolism Both epidemiological [1, 2] and experimental studies [3, 4] have illustrated that adverse environmental influences during the early. Emerging studies [9, 11,12,13] have shown that maternal PRD increases the risk of metabolic dysfunction in adulthood, the mechanisms during the early life of offspring are still poorly understood. ERNA transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription [20,21,22], which can be applied to understanding the transcriptional regulation of disease, like tumorigenesis [23, 24]
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