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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; Smith, Noel H.; Dekker Nitert, Marloes LU ; Ackers-Johnson, Matthew; Uribe-Lewis, Santiago; Ito, Yoko; Jones, R. Huw; Marquez, Victor E.; Cairns, William and Tadayyon, Mohammed, et al. (2011) In Proceedings of the National Academy of Sciences 108(13). p.5449-5454
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... (More)
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. (Less)
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publication status
published
subject
keywords
maternal nutrition, developmental programming, DNA methylation, histone, modifications, diet-gene interactions
in
Proceedings of the National Academy of Sciences
volume
108
issue
13
pages
5449 - 5454
publisher
National Acad Sciences
external identifiers
  • wos:000288894800060
  • scopus:79955096234
ISSN
1091-6490
DOI
10.1073/pnas.1019007108
language
English
LU publication?
yes
id
99436f99-8613-427d-bbd9-c75cfa91e83b (old id 1918842)
date added to LUP
2011-05-02 10:38:53
date last changed
2017-11-12 03:05:38
@article{99436f99-8613-427d-bbd9-c75cfa91e83b,
  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.},
  author       = {Sandovici, Ionel and Smith, Noel H. and Dekker Nitert, Marloes and Ackers-Johnson, Matthew and Uribe-Lewis, Santiago and Ito, Yoko and Jones, R. Huw and Marquez, Victor E. and Cairns, William and Tadayyon, Mohammed and O'Neill, Laura P. and Murrell, Adele and Ling, Charlotte and Constancia, Miguel and Ozanne, Susan E.},
  issn         = {1091-6490},
  keyword      = {maternal nutrition,developmental programming,DNA methylation,histone,modifications,diet-gene interactions},
  language     = {eng},
  number       = {13},
  pages        = {5449--5454},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets},
  url          = {http://dx.doi.org/10.1073/pnas.1019007108},
  volume       = {108},
  year         = {2011},
}