DNA methylation signatures link prenatal famine exposure to growth and metabolism

Elmar W. Tobi, Jelle J. Goeman, Ramin Monajemi, Hongcang Gu, Hein Putter, Yanju Zhang, Roderick C. Slieker, Arthur P. Stok, Peter E. Thijssen, Fabian Müller, Erik W. van Zwet, Christoph Bock, Alexander Meissner, L. H. Lumey, P. Eline Slagboom and Bastiaan T. Heijmans ()
Additional contact information
Elmar W. Tobi: Molecular Epidemiology, Leiden University Medical Center
Jelle J. Goeman: Medical Statistics and Bioinformatics, Leiden University Medical Center
Ramin Monajemi: Medical Statistics and Bioinformatics, Leiden University Medical Center
Hongcang Gu: The Broad Institute of MIT and Harvard
Hein Putter: Medical Statistics and Bioinformatics, Leiden University Medical Center
Yanju Zhang: Molecular Epidemiology, Leiden University Medical Center
Roderick C. Slieker: Molecular Epidemiology, Leiden University Medical Center
Arthur P. Stok: Molecular Epidemiology, Leiden University Medical Center
Peter E. Thijssen: Molecular Epidemiology, Leiden University Medical Center
Fabian Müller: Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics
Erik W. van Zwet: Medical Statistics and Bioinformatics, Leiden University Medical Center
Christoph Bock: Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics
Alexander Meissner: The Broad Institute of MIT and Harvard
L. H. Lumey: Molecular Epidemiology, Leiden University Medical Center
P. Eline Slagboom: Molecular Epidemiology, Leiden University Medical Center
Bastiaan T. Heijmans: Molecular Epidemiology, Leiden University Medical Center

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6592

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