Working with collaborators from across Oxford (Thomas Milne, Nick Crump, James McCullagh, Roman Fisher, Marjorie Fournier), in Cambridge (Sophie Trefely), and at Great Ormond Street Hospital (Steve Krywawych), the title of the two DPAG-based researchers' paper is: 'Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation'.
Their research used a mouse model of a rare metabolic disease, propionic acidaemia (PA), to unravel new epigenetic mechanisms that impact the heart, and have broader relevance to health and disease. “Our motivation for this project was two-fold. To better understand the disease mechanisms in PA, still an uncurable inherited disease, and to gain insight into processes that may impact other forms of cardiac disease. Indeed, much of our understanding of cardiac biology stems from work on rare arrhythmias or myopathies. This is another example of the importance of studying rare diseases, an under-funded area of science”, said principal investigator on the project, Pawel Swietach.
The research utilised the hypomorphic mouse model of PA because it offers unprecedented insights into the effects of disrupted propionyl-CoA metabolism in vivo. KC and colleagues focused on the heart, as mortality in many patients with PA is associated with cardiac dysfunction. Surrogates of elevated propionyl-CoA levels have been reported in diseases, such as diabetes, and as a product of gut microbiome activity, which raises the possibility that the link between propionate metabolism and gene expression may have broad implications on health and disease.
KC Park comments, ‘Alterations in gene expression within the heart constitute a central mechanism leading to cardiac dysfunction. Through a rare disease model, we've uncovered novel pathways by which metabolites epigenetically drive changes in gene expression, contributing to heart disease. These mechanisms hold potential implications for broader cardiometabolic syndromes. This project has been an extraordinary journey, and it's been a pleasure working with an incredible team of mentors and collaborators. Training in a variety of research approaches has been thoroughly enjoyable as an early-career scientist. I am truly grateful to the charities (British Heart Foundation, Propionic Acidemia Foundation, Metabolic Support UK, Organic Acidemia Association) and their patrons, without whose generosity this research would not have been possible.’
Read the paper here: https://www.nature.com/articles/s44161-023-00365-0