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

Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets
Ionel Sandovicia,b,1, Noel H. Smithc,1, Marloes Dekker Nitertd, Matthew Ackers-Johnsonc, Santiago Uribe-Lewise, Yoko Itoe, R. Huw Jonesc, Victor E. Marquezf, William Cairnsg, Mohammed Tadayyong, Laura P. O’Neillh, Adele Murrelle, Charlotte Lingd, Miguel Constânciaa,b,1,2, and Susan E. Ozannec,1,2
+ Author Affiliations

aMetabolic Research Laboratories, Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, United Kingdom;
bCentre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
cMetabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 OQQ, United Kingdom;
dDiabetes and Endocrinology Research Unit, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden;
eCancer Research United Kingdom Cambridge Research Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
fChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702;
gBiological Reagents and Assay Development, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom; and
hChromatin and Gene Expression Group, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom
Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved February 11, 2011 (received for review December 20, 2010)

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.