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Charlotte Ling

Charlotte Ling

Professor

Charlotte Ling

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

Author

  • Ionel Sandovici
  • Noel H. Smith
  • Marloes Dekker Nitert
  • Matthew Ackers-Johnson
  • Santiago Uribe-Lewis
  • Yoko Ito
  • R. Huw Jones
  • Victor E. Marquez
  • William Cairns
  • Mohammed Tadayyon
  • Laura P. O'Neill
  • Adele Murrell
  • Charlotte Ling
  • Miguel Constancia
  • Susan E. Ozanne

Summary, in English

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2011

Language

English

Pages

5449-5454

Publication/Series

Proceedings of the National Academy of Sciences

Volume

108

Issue

13

Document type

Journal article

Publisher

National Academy of Sciences

Topic

  • Endocrinology and Diabetes

Keywords

  • maternal nutrition
  • developmental programming
  • DNA methylation
  • histone
  • modifications
  • diet-gene interactions

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1091-6490