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PreprintCited by 5Advanced Proteomics Techniques and ApplicationsCardiac Fibrosis and RemodelingCongenital heart defects research

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A Ratiometric Catalog of Protein Isoform Shifts in the Cardiac Fetal Gene Program

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Han, Yu, Binti, Shaonil, Wennersten, Sara A., Pandi, Boomathi, Ng, Dominic C. M., Lau, Edward, Lam, Maggie P. Y.·2024·JCI Insight
DOI 10.1101/2024.04.09.588716PMC PMC12487847

Preprint — published as 10.1172/jci.insight.184309 · Paper page

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Abstract

Pathological cardiac remodeling is associated with the reactivation of fetal genes, yet the extent of the heart’s fetal gene program and its impact on proteome compositions remain incompletely understood. Here, using a new proteome-wide protein ratio quantification strategy with mass spectrometry, we identify pervasive isoform usage shifts in fetal and postnatal mouse hearts, involving 145 pairs of highly homologous paralogs and alternative splicing-derived isoform proteins. Proteome-wide ratio comparisons readily rediscover hallmark fetal gene signatures in muscle contraction and glucose metabolism pathways, while revealing novel isoform usage in mitochondrial and gene expression proteins, including PPA1/PPA2, ANT1/ANT2, and PCBP1/PCBP2 switches. Paralogs with differential fetal usage tend to be evolutionarily recent, consistent with functional diversification. Alternative splicing adds another rich source of fetal isoform usage differences, involving PKM M1/M2, GLS-1 KGA/GAC, PDLIM5 long/short, and other spliceoforms. When comparing absolute protein proportions, we observe a partial reversion toward fetal gene usage in pathological hearts. In summary, we present a ratiometric catalog of paralogs and spliceoform pairs in the cardiac fetal gene program. More generally, the results demonstrate the potential of applying the proteome-wide ratio test concept to discover new regulatory modalities beyond differential gene expression.

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Metadata

Authors
Han, Y., Binti, S., Wennersten, S. A., Pandi, B., Ng, D. C. M., Lau, E., & Lam, M. P. Y.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
Lam, Maggie P. Y.
ORCID
Venue
JCI Insight
Publisher
openRxiv
Published
2024-04-10
Volume
10
Issue
20
ISSN
2379-3708 (ISSN-L)
DOI
10.1101/2024.04.09.588716
PMC
PMC12487847
OpenAlex
W4413044285
Cited by
5
References
1
Citations by year
2026: 5
FWCI
1.27
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (25POST1372064)
  • National Institutes of Health (1r01hl169473-01a1)
  • National Heart, Lung, and Blood Institute (R01-HL169473, R00HL144829, R01HL141278)
  • National Institute of General Medical Sciences (R01GM144456, R35GM146815)
Topics
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
paralogs, alternative splicing, cardiac remodeling, PDLIM5, mitochondrial proteins, glucose metabolism, muscle contraction, mouse heart

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