DNA methylation signatures link prenatal famine exposure to growth and metabolism

TLDR

Periconceptional diet can persistently alter DNA methylation with phenotypic consequences, yet a comprehensive human assessment of prenatal malnutrition‑associated differentially methylated regions (P‑DMRs) remains lacking. This study aims to map genome‑wide DNA methylation changes in whole blood following periconceptional famine exposure during the Dutch Hunger Winter. Whole‑blood samples were profiled genome‑scale to identify differentially methylated regions associated with famine exposure. The analysis showed that P‑DMRs preferentially occur at regulatory regions with intermediate methylation, are linked to genes differentially expressed in early development, and are enriched in growth and metabolism pathways; P‑DMRs in INSR and CPT1A exhibit enhancer activity and associate with birth weight and LDL cholesterol, indicating that prenatal malnutrition epigenetically promotes adverse metabolic phenotypes later in life.

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.