Nutrition-sensitive epigenetic mechanisms in the early human embryo - developing insights from stem cell and organoid models
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 will allow me to gain a deeper understanding of early embryonic epigenetic processes and the techniques that are available to interrogate these, through joining a group at the University of Cambridge that has pioneered work in this area. I will use this knowledge and links with researchers working in the Department of Genetics to devise experiments to test key aspects of our nutritional programming hypothesis in developmental cell and gastruloid models, enabling me to probe the roles of specific nutrients, genetic variation, specific transcription factors (e.g. ZFPs), and chromatin remodelling via histone modifications.
1.1 Normal biological development and functioning / Research Grant