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  • Project No: 38
  • Awards: Pump-priming Awards

In cardiomyocytes, disturbances to metabolic fluxes can dynamically change the state of chromatin by modifying histones. Since the ensuing transcriptional responses may contribute towards cardiac disease, a priority is to attribute specific types of histone modifications to pathological remodelling. We aim to address this by studying the epigenetic actions of different acyls using mouse models that produce an appropriate biochemical milieu. As proof-of-principle, we developed an interest in propionate because this short-chain acyl features in multiple metabolic pathways and can modify proteins. Elevations of propionate have been reported in cardiometabolic disorders, but how this disturbance contributes to dysfunction is unclear. To that end, we used a mouse model of propionic acidaemia (PA): an inborn error of metabolism arising from defective propionyl-CoA carboxylase. This project will use metabolomics to trace the fate of propiogenic substrates as they pass through metabolic pathways and proteomics to inform which histone residues are modified.