Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
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After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly.
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Key genes in the maturation of fatty acid metabolism, sarcomere, and ion channels were upregulated in cardiomyocytes from hvCTS and hvCOC relative to those from CS and hvCAS.
“Key genes in the maturation of fatty acid metabolism, sarcomere, and ion channels were also upregulated in CMs from the hvCTS and hvCOC relative to those from the CS and hvCAS (Figure 3C).11,23,36”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [36]
The Discussion (Fig. 9; page unavailable) identifies metabolism, sarcomere, and ion-channel genes as important to cardiomyocyte maturation. The Results section on stage-specific transcriptomic regulation reports changes in some of these genes in murine Srf-knockout cardiomyocytes, but it does not support the claimed upregulation in hvCTS and hvCOC relative to CS and hvCAS. (LLM, conf=0.84)
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- Authors
- Guo, Y., Jardin, B. D., Zhou, P., Sethi, I., Akerberg, B. N., Toepfer, C. N., Ai, Y., Li, Y., Ma, Q., Guatimosim, S., Hu, Y., Varuzhanyan, G., VanDusen, N. J., Zhang, D., Chan, D. C., Yuan, G.-C., Seidman, C. E., Seidman, J. G., & Pu, W. T.
- Affiliations
- Boston Children's Hospital (US)
- Boston University (US)
- Dana-Farber Cancer Institute (US)
- Centre for Human Genetics (GB)
- California Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Pu, William T.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-09-21
- Volume
- 9
- Issue
- 1
- Pages
- 3837-3837
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6155060
- OpenAlex
- W2889940320
- Cited by
- 96
- References
- 65
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 13 · 2022: 17 · 2021: 13 · 2020: 13 · 2019: 6 · 2018: 1
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (2UM1 HL098166)
- American Heart Association (17IRG33410894)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- serum response factor, cardiomyocyte maturation, sarcomere assembly, mitochondrial biogenesis, mitochondrial dynamics, T-tubules, cardiomyocyte hypertrophy, chromatin occupancy, transcriptional regulation, neonatal cardiomyocytes, CRISPR-Cas9 screen
- MeSH terms
- Animals, Animals, Newborn, Chromatin, Female, Gene Expression Regulation, Male, Mutagenesis, Mice, Knockout, Serum Response Factor, Myocytes, Cardiac, Mice, Transcriptome, CRISPR-Cas Systems
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