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

Elmar W Tobi,Christoph Bock,Yanju Zhang,Arthur P Stok,P Eline Slagboom,Jelle J Goeman,Peter E Thijssen,Erik W Van Zwet,Fabian Müller,Hein Putter,Roderick C Slieker,Bastiaan T Heijmans,Ramin Monajemi,L H Lumey,Alexander Meissner,Hongcang Gu

doi:10.1038/ncomms6592

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.

Highlights

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences
Using a step-wise analysis strategy based on extensive genomic annotation[16], followed by technical and biological validation of selected individual regions, we identify genomic characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs)
For the genomescale representation bisulfite sequencing (RRBS) measurements, we focused on a subset of 24 sibling pairs (Supplementary Fig. 1A.1) with a o5-year age difference and an equal number of male and female pairs as well as an equal number of pairs with the control siblings conceived and born before or after the famine period to minimize the potential effects of these possible confounders (Supplementary Table 1)

Summary

Introduction

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. The subsequent observation of differential DNA methylation after prenatal famine exposure at promoters and imprinted regions regulating genes involved in metabolism suggested a role for epigenetic mechanisms in these phenotypic associations[6,7]. These findings may have a broader significance since similar health outcomes and DNA methylation differences were reported for common adverse prenatal conditions, including exposure to gestational diabetes[8,9] and maternal smoking during pregnancy[10,11].

Methods

Results

Conclusion