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PXD043513

PXD043513 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDisrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
DescriptionPropionate 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-07
AnnouncementXMLSubmission_2024-10-07_13:49:25.311.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitteriolanda Vendrell
SpeciesList scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationListacetylated residue; monohydroxylated residue; 5x(13)C,1x(15)N labeled L-valine; 6x(13)C labeled L-isoleucine
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-07-03 11:09:21ID requested
12024-10-07 13:49:25announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Heart failure, Histone, Contraction, Epigenetics,Propionic acidemia
Contact List
Pawel Swietach
contact affiliationDivision of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
contact emailpawel.swietach@dpag.ox.ac.uk
lab head
iolanda Vendrell
contact affiliationTarget Discovery Institute, NDMRB
contact emailiolanda.vendrell@ndm.ox.ac.uk
dataset submitter
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