PXD043513-1

PXD043513 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-03 11:09:21	ID requested
⏵ 1	2024-10-07 13:49:25	announced

Dataset with its publication pending

submitter keyword: Heart failure, Histone, Contraction, Epigenetics,Propionic acidemia

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

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PRIDE project URI

• PRIDE
  1. PXD043513
     1. Label: PRIDE project
     2. Name: Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation