Nutrition-sensitive epigenetic mechanisms in the early human embryo - developing insights from stem cell and organoid models

Each cell in our body contains an identical DNA blueprint inherited from our parents (excepting sperm and eggs that contain half a copy). The decoding and expression of these genes needs to be finely regulated to make different cell types and govern cell metabolism. This is achieved by 'epigenetic' modifications to the DNA.

One form of epigenetic regulation is achieved by marking certain regions of the genome with chemical 'methyl group' tags that tend to block gene expression. Most of this DNA methylation is faithfully inherited every time cells divide and so acts as a semi-permanent regulator of how genes operate.

When sperm fertilises egg the methylation marks on each are largely erased in the first few days after conception and a new 'methylome' is created for the embryo. We have studied a seasonal experiment of nature in rural Gambia whereby conceptions occur against very different dietary and nutritional conditions. We have shown that certain 'environmentally- sensitive hotspots' across the genome are very sensitive to the baby's season of conception.

These hotspots have a characteristic signature indicating that they are permanently altered in the very early embryo. We believe that they may have evolved to SENSE the mother's (nutritional) environment, RECORD that information, and ADAPT the developing fetus to be best suited to the predicted future conditions. If the future conditions are different these changes may become maladaptive and cause disease.

We have already shown that certain of these variable regions may be linked to diseases such as obesity, cancer and thyroid disease.

Our Gambian natural experiment has provided vital clues about environmentally sensitive molecular processes occurring in the early human embryo. However, in order to fully understand these processes and to confirm specific nutrient effects, we need to test our discoveries in embryonic cells and associated structures. This award would allow me to spend time in the Department of Genetics at the University of Cambridge.

This group has pioneered work investigating molecular processes in the early embryo and they therefore make ideal hosts to guide me in developing the cutting edge experiments that are required to take our Gambian nutritional epigenetics research to the next stage.