Nutrition and the epigenome: early environmental factors influencing human developmental programming
Medical Research Council
London School of Hygiene and Tropical Medicine
A seasonal 'experiment of nature' in rural Gambia has revealed the presence of DNA methylation (DNAm) hotspots sensitive to periconceptional environment. These are enriched for metastable epialleles, endogenous retroviruses and parent-of-origin-specific methylation (PofOm) suggesting establishment in the early embryo. This is further supported by analysis of public IVF and gametic DNAm datasets which show distinctive patterns of early embryo DNAm dynamics along with enrichment for regions hypomethylated in sperm. Several loci are linked to disease outcomes, including obesity, thyroid disease and cancer. Genetic analysis suggests the greater part of DNAm variance at many season-of-conception (SoC)-associated loci is explained by gene-environment interactions, suggesting they may have evolved to sense the environment, record the information and adapt the phenotype accordingly. Such 'programmed' epigenetic states would be maladaptive if there is a mismatch with the postnatal environment, with implications for the developmental origins of health and disease. This grant seeks to establish a unique prospective SoC cohort of 600 babies to assess exposures within +/-15 days of conception in order to: a) define nutritional and other SoC exposures (methylation pathway metabolites; agnostic metabolomics; fecal microbiome); b) understand and characterise key features of SoC-sensitive loci to gain insights into genetic and other mechanisms underpinning their establishment; c) confirm and delineate the role of gene-environment interactions as a potential driver of SoC-sensitivity and look for signatures of genetic selection; d) assess the influence of SoC on the placental transcriptome (trophoblasts/mesenchymal cells) with particular attention to genomic imprinting and PofOm; e) assess effects of the above on placental and fetal growth and development. This work will establish an open-access Early Developmental Epigenetic BioResource for researchers worldwide.
2.4 Surveillance and distribution / Research Grant