Dataset Information

Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.

ABSTRACT: 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.

SUBMITTER: Sandovici I

PROVIDER: S-EPMC3069181 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.

Sandovici Ionel I Smith Noel H NH Nitert Marloes Dekker MD Ackers-Johnson Matthew M Uribe-Lewis Santiago S Ito Yoko Y Jones R Huw RH Marquez Victor E VE Cairns William W Tadayyon Mohammed M O'Neill Laura P LP Murrell Adele A Ling Charlotte C Constância Miguel M Ozanne Susan E SE

Proceedings of the National Academy of Sciences of the United States of America 20110308 13

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 ...[more]

PMID: 21385945

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Project description:BackgroundDNA methylation-based epigenetic age measures have been used as biological aging markers and are associated with a healthy lifespan. Few population-based studies have examined the relation between diet and epigenetic age acceleration.ObjectivesWe aimed to investigate the relation between diet quality and epigenetic age acceleration.MethodsWe analyzed data from 1995 participants (mean age, 67 years; 55% women) of the Framingham Heart Study Offspring Cohort. Cross-sectional associations between the Dietary Approaches to Stop Hypertension (DASH) score and 3 whole-blood DNA methylation-derived epigenetic age acceleration measures-Dunedin Pace of Aging Methylation (DunedinPoAm), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA)-were examined. A mediation analysis was conducted to assess the mediating role of epigenetic age acceleration in relation to DASH and all-cause mortality.ResultsA higher DASH score was associated with lower levels of DunedinPoAm (β = -0.05; SE = 0.02; P = 0.007), GrimAA (β = -0.09; SE = 0.02; P < 0.001), and PhenoAA (β = -0.07; SE = 0.02; P = 0.001). All 3 epigenetic measures mediated the association between the DASH score and all-cause mortality, with mean proportions of 22.1% for DunedinPoAm (Pmediation = 0.04), 45.1% for GrimAA (Pmediation = 0.001), and 22.9% for PhenoAA (Pmediation = 0.03). An interaction was observed between the DASH score and smoking status in relation to the epigenetic aging markers. The association between the DASH score and epigenetic aging markers tended to be stronger in "ever-smokers" (former and current smokers) compared to "never-smokers." The proportions of mediation were 31.3% for DunedinPoAm, 46.8% for GrimAA, and 10.3% for PhenoAA in ever-smokers, whereas no significant mediation was observed in never-smokers.ConclusionsHigher diet quality is associated with slower epigenetic age acceleration, which partially explains the beneficial effect of diet quality on the lifespan. Our findings emphasize that adopting a healthy diet is crucial for maintaining healthy aging.

Dataset Information

Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.

Publications

Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.

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