Diet at conception could have long-lasting effects

Dr. Robert Waterland, associate professor of pediatrics – nutrition at  Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital, one of the leaders of the study said, “There are around 20,000 genes in the human genome. So for our two groups, taking different approaches, to identify this same gene as the top epiallele was like both of us digging into different sides of a gigantic haystack containing 20,000 needles and finding the exact same needle.”

This finding suggests that the epigenetic regulation of VTRNA2-1 is particularly sensitive to a mother’s environment around the time of conception.

How genes are inherited

Except for genes on sex chromosomes, mammals inherit two copies of all our genes, one from our mother and one from our father. In most cases, these function equally.  However, VTRNA2-1 belongs to a special class of genes that are normally expressed from only the maternal or paternal copy. These are called imprinted genes, because their parental lineage is imprinted with epigenetic marks inherited from the sperm or egg. VTRNA2-1 is the first example of an imprinted metastable epiallele.

The other leader of the study, Professor Andrew Prentice at the London School of Hygiene & Tropical Medicine, and head of the MRC International Nutrition Group said, “Our results show that the methylation marks that regulate VTRNA2-1 imprinting are lost in some people, and that this ‘loss of imprinting’ is determined by maternal nutrition around the time of conception. These are large changes in gene methylation that affect a substantial subset of individuals.”

Occurs systemically

The investigators showed that loss of imprinting at VTRNA2-1 is not restricted to certain cell types, but occurs systemically (affecting all the cells of the body). Moreover, they showed that VTRNA2-1 loss of imprinting is stable from childhood to adulthood, indicating that the effect of mother’s nutrition around the time of conception likely lasts for a lifetime.

In the last few years, three different studies have shown that increased methylation at the VTRNA2-1 tumor suppressor is a risk factor for acute myeloid leukemia, lung, and esophageal cancer, respectively. Individuals with VTRNA2-1 loss of imprinting effectively have a double-dose of this anti-cancer gene, so the authors hypothesize that this congenital ‘abnormality’ may actually provide a degree of protection from cancer. Studies are underway to test whether methylation at VTRNA2-1 can be used as a screening test to predict one’s risk of cancer.

Others who took part in this work include Noah J. Kessler, Eleonora Laritsky and Maria S. Baker of the Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital, Cristian Coarfa of the department of molecular and cellular biology at Baylor, Hector Hernandez-Vargas and Zdenko Herceg of the International Agency for Research on Cancer at Lyon, France; Matt J. Silver, Branwen J. Hennig, Paula Dominguez-Salas, Sophie E. Moore and Anthony J. Fulford, all of the MRC National Nutrition Group at the London School of Hygiene & Tropical Medicine, Jovita M.Castelino and Michael N. Routledge of the University of Leeds in the United Kingdom, Yun Yun Gong of Queen’s University in Belfast, United Kingdom; and Yong Sun Lee and Kwanbok Lee of The University of Texas Medical Branch at Galveston.

Funding for this work came from the USDA (CRIS 6250-51000-055) and the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK081557). The Gambian study was supported by Wellcome Trust (Grant WT086369MA) and core funding MCA760-5QX00 to the International Nutrition Group by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, The IARC grant and a Grand Challenges Exploration grant from the Bill and Melinda Gates Foundation.