Journal article
Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
- Abstract:
- Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 10.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s44161-023-00365-0
Authors
+ European Society Council Consolidator Award
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- Funding agency for:
- Swietach, P
- Grant:
- 723997
+ Kay Kendall Leukaemia Fund Intermediate Fellowship
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- Funding agency for:
- Crump, NT
- Grant:
- KKL1443
+ British Heart Foundation
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- Grant:
- RG/15/9/31534
- FS/16/59/32735
- Funding agency for:
- Park, KC
+ Biotechnology and Biological Sciences Research Council
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- Funding agency for:
- Choeng, YJ
- Trefely, S
- Grant:
- P013406/1
+ Medical Research Council
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- Funding agency for:
- Crump, NT
- Milne, TA
- Grant:
- MC_UU_00016/6
- Publisher:
- Springer Nature
- Journal:
- Nature Cardiovascular Research More from this journal
- Volume:
- 2
- Issue:
- 12
- Pages:
- 1221-1245
- Publication date:
- 2023-11-23
- Acceptance date:
- 2023-10-15
- DOI:
- EISSN:
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2731-0590
- Language:
-
English
- Pubs id:
-
1544841
- Local pid:
-
pubs:1544841
- Deposit date:
-
2023-10-16
- ARK identifier:
Terms of use
- Copyright holder:
- Park et al.
- Copyright date:
- 2023
- Rights statement:
- © 2023, The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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