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Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation [ChIP-Seq 2]

ABSTRACT: Propiogenic substrate catabolism and gut bacteria produce propionate, a post-translational protein modifier. Here, using a mouse model of propionic acidaemia (PA), we characterise how disturbances to propionate metabolism modify histones and affect cardiac gene expression and function. Plasma propionate was raised in PA mice, but male hearts accumulated a smaller propionyl-CoA excess, correlating with -alanine build-up. Raising -alanine experimentally in myocytes cultured under propionate-stress reduced propionyl-CoA and partially reversed the propionate-evoked metabolic disturbance. Female PA hearts manifested a moderate diastolic dysfunction phenotype, with raised diastolic [Ca2+], expanded end-systolic ventricular volume, and reduced stroke volume. Differentially-expressed genes included Pde9a and Mme that relate to contractile dysfunction through down-scaled cGMP signalling, consistent with phosphoproteome changes. Propionate was traced to histone H3 propionylation and increased acetylation genome-wide, including at Pde9a and Mme promoters, with more pronounced effects in female PA hearts. We link perturbed propionate metabolism to epigenetic changes that impact cardiac function.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE205837 | GEO | 2023/09/28

REPOSITORIES: GEO

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Project description:Propionate is a common three-carbon intermediate produced from the breakdown of propiogenic substrates, such as branched-chain amino acids and odd-numbered fatty acids, and by gut bacteria. Propionate can chemically modify proteins, and if this involves histones, it may underpin a disease-relevant link between short-chain acyls and gene expression in the heart. Here, we sought to characterize how propionate-dependent modifications to histones affect cardiac gene expression and contractile function in a mouse model producing elevated levels of propionate/propionyl-CoA. An adult mouse model of propionic acidaemia (PA) was used to investigate how propionate affects histones and gene expression in the heart, an organ strongly affected in PA patients. Mass spectrometry confirmed elevated plasma propionate in 8-week PA mice, reaching levels detected in PA patient serum. Metabolomic analyses confirmed a metabolic signature of PA, but male mice had enhanced propionate processing towards -alanine. Female PA hearts had expanded end-diastolic and end-systolic volumes, and weaker systolic contractions, without major electrocardiographic changes. Ca2+ signals were deranged in female PA mice (raised diastolic Ca2+), consistent with contractile dysfunction. Differentially-expressed genes (DEGs) included Pde9a and Mme, previously linked to cardiac dysfunction. These DEGs also responded to 48-h culture of wild-type myocytes with propionate as well as butyrate, an HDAC inhibitor, suggesting a role for increased histone acetylation alongside propionylation in inducing these genes. Indeed, histone acetylation (H3K27ac) and propionylation were elevated genome-wide in the PA heart and at the promoters of Pde9a and Mme. These propionate-associated epigenetic responses were more pronounced in female PA mice. The greater prominence of epigenetic, transcriptional, and functional responses in female PA mice, despite a mostly sex-indiscriminate overall metabolic milieu, argues that histone acylation plays a defining role in the cardiac phenotype. We conclude that perturbed propionate metabolism in vivo alters histone acylation and gene expression, which impacts cardiac contractile function.

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Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation [ChIP-Seq 2]

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