DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children

Authors: CANDLER, TOBY - London School Of Hygiene & Tropical Medicine; KESSLER, NOAH - University Of Cambridge; GUNASEKARA, CHATHURA - Children'S Nutrition Research Center (CNRC); WARD, KATE - University Of Southampton; JAMES, PHILIP - London School Of Hygeine; LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); DYER, ROGER - British Columbia Children'S Hospital Research Institute; ELANGO, RAJAVEL - British Columbia Children'S Hospital Research Institute; JEFFRIES, DAVID - London School Of Hygiene & Tropical Medicine; WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC); MOORE, SOPHIE - London School Of Hygiene & Tropical Medicine; LUDGATE, MARIAN - Cardiff University; PRENTICE, ANDREW - London School Of Hygiene & Tropical Medicine; SILVER, MATT - London School Of Hygiene & Tropical Medicine

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/16/2021
Publication Date: 11/5/2021
Citation: Candler, T., Kessler, N., Gunasekara, C., Ward, K., James, P., Laritsky, E., Baker, M., Dyer, R., Elango, R., Jeffries, D., Waterland, R., Moore, S., Ludgate, M., Prentice, A., Silver, M. 2021. DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children. Science Advances. 7(45). Article eabj1561. https://doi.org/10.1126/sciadv.abj1561.
DOI: https://doi.org/10.1126/sciadv.abj1561

Interpretive Summary: Epigenetics is a system for molecular marking of DNA – it tells the different cells in the body which genes to turn on or off in that cell type. A key epigenetic mechanism is methylation of cytosine nucleotides in DNA. Once established during development, DNA methylation can stably silence gene expression. Over the last decade we have identified human genomic regions that show interindividual differences in DNA methylation that are consistent across all tissues and cell types in the body. We refer to these as correlated regions of systemic interindividual epigenetic variation (CoRSIVs). Early embryonic establishment of DNA methylation at CoRSIVs is influenced by maternal nutrition before pregnancy. To better understand the long-term consequences of such epigenetic changes, we focused on a CoRSIV in the PAX8 gene, which is known to regulate thyroid development. Using an existing genome-scale data set on DNA methylation in blood of 500 Gambian children at age 2, we identified two groups of 60 children each, one with the highest methylation at PAX8 ("high"), and the other with the lowest ("low"). Thyroid function, growth, and body composition was assessed when these children were age 5-8. Compared to children with the highest PAX8 methylation, lower PAX8 methylation at age 2 predicted greater thyroid volume, higher levels of thyroid hormone, and lower fat mass in later childhood. These findings demonstrate long-term metabolic consequences of individual epigenetic variation, and highlight a causal pathway by which periconceptional nutrition can impact health in later life.

Technical Abstract: PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and PAX8 gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that PAX8 hypomethylation at age 2 years is associated with a 21% increase in thyroid volume and an increase in free thyroxine (T4) at 5 to 8 years, the latter equivalent to 8.4% of the normal range. Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density. Furthermore, offspring PAX8 methylation was associated with periconceptional maternal nutrition, and methylation variability was influenced by genotype, suggesting that sensitivity to environmental exposures may be under partial genetic control. Together, our results demonstrate a possible link between early environment, PAX8 gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease.