HDHL DIMENSION: Dietary induced methylome and transcriptome dynamics assessing nutrition impacts on cardiovascular and metabolic health

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Cardiovascular and metabolic diseases are a primary cause of morbidity and mortality worldwide. Diet is a major risk factor for cardio-metabolic health, but is challenging to study in part because metabolic response to diet is highly individualised. Characterising the molecular pathways that mediate personalised responses to diet is critical to effectively tackle the current epidemic. Epigenetic mechanisms are key regulators of gene function that can change in response to external stimuli, including diet. However, longitudinal studies of epigenetic dynamics in response to diet are rare. Our hypothesis is that the identification of dietary induced epigenetic marks together with epigenetic signatures of cardio-metabolic traits explain inter-individual variability in metabolic response to diet and its downstream effects on health. The DIMENSION consortium will test this hypothesis by investigating dynamically the causal impacts of dietary intake on epigenetic regulation of gene function across tissues, and their impact on subsequent cardio-metabolic health outcomes. The proposal will explore the gene regulatory and functional pathways that occur immediately following food intake in the postprandial state, as well as with habitual dietary intakes. We will test postprandial metabolic responses that have been largely overlooked, despite revealing multiple aspects of diet induced metabolic health that would not be detectable from studying fasting status alone. Further, humans spend the majority of their lives in the postprandial glycemic and lipemic state, which are themselves independent risk factors of cardiovascular disease. The work programme is based on: (i) targeted postprandial and nutritional intervention studies to tackle the causal relationships between diet, epigenetic modifications and gene function, in combination with (ii) state-of-the-art analyses to characterize the links between diet, epigenetics, and cardio-metabolic health using novel diet measures including metabolomics in extensively studied cohorts, and (iii) functional follow-up experiments assessing the impact of diet-induced epigenetic and transcriptomic signals at the level of cells, within and across tissues. Using complementary approaches, the DIMENSION consortium will deliver novel mechanistic insights into how exactly nutritional modifications can modulate the regulatory and functional genome to promote cardio-metabolic health. These insights will complement traditional population-based guidelines and inform the rapidly evolving area of individualised nutrition-based strategies.