Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline

Flitton, Miles; Rielly, Nicholas; Warman, Rhian; Warden, Donald; Smith, A. David; Macdonald, Ian A.; Knight, Helen Miranda

Abstract

Low homocysteine levels and B vitamin treatment are reported to protect against declining cognitive health. Both B vitamins and homocysteine are involved in the production of S-adenosylmethionine, a universal methyl donor essential for the process of DNA methylation. We investigated the effect of a damaging coding variant within the DNA methyltransferase gene, DNMT3L (R278G, A/G) by examining B vitamin intake, homocysteine levels, cognitive performance, and brain atrophy in individuals in the VITACOG study of Mild Cognitive Impairment and the TwinsUK cohort. In the VITACOG study, individuals who received a two- year treatment of B vitamins and carried the G allele, showed better ‘visuospatial associative memory’ and slower rates of brain atrophy. In the TwinsUK study, improved ‘visuospatial associative memory’ was evident in individuals who reported regular vitamin intake and were A/A homozygotes. In silico modelling indicated that R278G disrupts protein interaction between DNMT3L and DNMT3A, affecting the DNMT3A-3L-H3 complex required for DNA methylation. These findings show that vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.

Citation

Flitton, M., Rielly, N., Warman, R., Warden, D., Smith, A. D., Macdonald, I. A., & Knight, H. M. (2019). Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline. Neurobiology of Aging, 78, 64-73. https://doi.org/10.1016/j.neurobiolaging.2019.02.001

• Journal Article Type: Article
• Acceptance Date: Feb 8, 2019
• Online Publication Date: Feb 13, 2019
• Publication Date: Jun 1, 2019
• Deposit Date: Feb 14, 2019
• Publicly Available Date: Feb 14, 2020
• Journal: Neurobiology of Aging
• Print ISSN: 0197-4580
• Electronic ISSN: 1558-1497
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 78
• Pages: 64-73
• DOI: https://doi.org/10.1016/j.neurobiolaging.2019.02.001
• Keywords: Developmental Biology; Ageing; General Neuroscience; Geriatrics and Gerontology; Clinical Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/1546943
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0197458019300417?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline; Journal Title: Neurobiology of Aging; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.neurobiolaging.2019.02.001; Content Type: article; Copyright: © 2019 Elsevier Inc. All rights reserved.