Nutrition and the epigenome: early environmental factors influencing human developmental programming

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 methyl groups 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.

In this grant, we seek to better understand HOW diet affects the laying down of these methylation marks, WHICH areas of the methylome are especially sensitive to such influences, HOW they influence the development of the placenta and fetus, and ultimately WHAT effects these changes have on the baby's development and life-long health.

To achieve this, we will follow rural Gambian families planning to conceive and collect data and blood samples within +/-15 days of conception to much better characterise the environmental factors that are driving the epigenetic changes we study. We will use advanced metabolomic methods to measure differences in the pathways required for DNA methylation and search for possible factors beyond diet (including pesticide and other toxic exposures, pharmaceuticals, etc). We will also search for seasonal differences in the mothers' gut microbiome to see if that may be influencing the changes we see.

We will use new finely-targeted epigenetic arrays to study our hotspots of interest and learn how and why they might have evolved, playing special attention to how these changes affect genomic processes (such as imprinting) that are crucial for placental (and hence fetal) development.

Finally we will examine the effects of these changes on the babies born in the new cohort and follow them into the future. This will create an open, accessible 'Early Developmental Epigenetic BioResource' for researchers worldwide.

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.

Our research on environmentally-modifiable methylation in the early human embryo lies at a nexus between discovery and implementation science. We have clear evidence that a baby's methylome is influenced by nutrition and/or other environmental exposures at conception. An increasing body of evidence suggests that this will affect placental and fetal development, and may programme future disease risk. The proposed research seeks to advance both elements; a) to better describe the critical environmental exposures and understand their mechanism(s) of action as well as their likely health consequences, and b) by doing so, to make progress towards optimising these processes through nutritional or other interventions.

1. Who will benefit from this research?

Timescale is key to answering this question. At present the chief beneficiaries are basic scientists ranging from (epi)geneticists to evolutionary, developmental and reproductive biologists. Our work already suggests the possibility of links to a range of health phenotypes: imprinting disorders, childhood and adult cancers, immune function, obesity and thyroid disease. It is important, for the time being, to recognise these possible implications without over-inflating any claims. However, if these links are confirmed by future work then the implications could be far reaching across many health sectors.

2. How will they benefit from this research?

Our working thesis is that processes have evolved to allow the early embryo to sense the environment, record that information in discrete environmentally-sensitive hotspots on the methylome, and thereby adapt the developmental trajectory of placenta and fetus with putative lifelong sequelae as captured by the development origins of health and disease (DOHaD) theory. Although discovered in rural Gambians we believe that the mechanism will be at play in parents worldwide. Existing theories suggest two possible variants of our sense-record-adapt concept: one would involve genetically-driven epigenetic variance that would be advantageous at the population level by creating a wider range of individuals as the substrate for natural selection (but would be detrimental for many individuals); the other proposes that the variants are intentional adaptations which will benefit health and survival so long as the environmental at conception is a good predictor of future environment (but become maladaptive otherwise).

If the first of these theories is true, then a range of developmental errors (ranging from mild to severe) might be more common in parents on poor diets or those exposed to environmental stressors/toxins. Identification of such effects and their triggers could have a profound impact by reducing a range of pregnancy pathologies.

Similarly, if the second proposed pathway holds true, this might offer the possibility of interrupting the intergenerational transmission of health deficits. For example, our work on POMC shows that the methylation of discrete loci in the promoter is sensitive to maternal diet at conception and is a strong predictor of childhood and adult obesity. This raises the possibility that dietary interventions targeted at the pre-conceptional period could reduce the obesity risk of offspring with potentially major implications for wealth and health, especially in advanced nations with a high burden of obesity.

Interventions to prevent neural tube defects offer a good exemplar of how such discoveries can benefit society. Initial association studies were backed by a series of increasingly large randomised trials that provided the required evidence for actions. Health campaigns (both governmental and non-governmental) were aligned to policy change (recommendation and provision of folic acid) that in turn has provided sales benefits for vitamin manufacturers. Adoption of food fortification in many countries has greatly reduced the personal and societal burden of NTDs with consequent health care savin