Propionic acidemia as a framework for understanding the impact of disturbed propionyl-CoA on histone modifications

Histone propionylation-the transfer of a three-carbon propionyl group from propionyl-CoA to lysine residues-is an emerging post-translational modification (PTM) with potential effects on gene expression. Interest in this PTM has grown because propionyl-CoA is at the interface between valine, isoleucine, methionine, and threonine catabolism, odd-chain fatty acid oxidation, gut-derived propionate assimilation, and anaplerotic entry into the tricarboxylic acid cycle. An informative context for studying the influence of disturbed propionyl-CoA metabolism on chromatin state and phenotype is propionic acidemia (PA), where loss-of-function mutations in genes coding propionyl-CoA carboxylase (PCC) lead to the accumulation of propiogenic substrates and propionyl-CoA. At least some of the clinical manifestations of PA (cardiomyopathy, arrhythmia, and neurological injury) may relate to altered histone propionylation, and a challenge is to distinguish these responses from metabolic toxicity. To that end, mouse models of PA are promising tools for connecting molecular-level histone changes to systems-level phenotypes. In this review, we describe recent advances in propionyl-CoA biology in the context of histone modifications and gene regulation. We present milestone studies that identified histone PTMs and described their association with phenotype. We also highlight emerging questions related to propionyl-CoA handling, its compartmentalization, and tissue specificity of actions, and discuss the relative contribution of histone propionylation versus other forms of acylation and broader metabolic stress. On balance, the literature supports a model in which propionyl-CoA exerts regulatory actions on chromatin state, but how this might be targeted therapeutically in PA and the implications for other metabolic disturbances remain important areas for further investigation.