PXD043513 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation |
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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-07 |
AnnouncementXML | Submission_2024-10-07_13:49:25.311.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | iolanda Vendrell |
SpeciesList | scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; |
ModificationList | acetylated residue; monohydroxylated residue; 5x(13)C,1x(15)N labeled L-valine; 6x(13)C labeled L-isoleucine |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-07-03 11:09:21 | ID requested | |
⏵ 1 | 2024-10-07 13:49:25 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Heart failure, Histone, Contraction, Epigenetics,Propionic acidemia |
Contact List
Pawel Swietach |
contact affiliation | Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. |
contact email | pawel.swietach@dpag.ox.ac.uk |
lab head | |
iolanda Vendrell |
contact affiliation | Target Discovery Institute, NDMRB |
contact email | iolanda.vendrell@ndm.ox.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD043513
- Label: PRIDE project
- Name: Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation