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Nat Commun. 2014 Nov 26;5:5592. doi: 10.1038/ncomms6592.

DNA methylation signatures link prenatal famine exposure to growth and metabolism.

Author information

1
Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
2
Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
3
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
4
1] Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands [2] Human Genetics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
5
Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
6
1] Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany [2] CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, 1090 Vienna, Austria [3] Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
7
1] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Stem cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
8
1] Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands [2] Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

Abstract

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.

PMID:
25424739
PMCID:
PMC4246417
DOI:
10.1038/ncomms6592
[Indexed for MEDLINE]
Free PMC Article

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