BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes
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Abstract
Background: Gene regulatory networks control tissue homeostasis and disease progression in a cell type–specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. Methods: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis. Results: Here, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b , and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity. Conclusions: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.
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JQ1-associated transcriptional changes in cardiomyocytes are modest compared with other cardiac cell populations.
“Given our observation that transcriptional changes associated with JQ1 in the cardiomyocyte (CM) compartment are modest compared to other cardiac cell populations4,11”
From Chromatin remodelling drives immune cell–fibroblast communication in heart failure (2024) · cites this paper as [11]
The Results section reports that JQ1-treated sham-operated mouse hearts showed no dramatic transcriptional changes. The Discussion suggests that JQ1’s dominant targets in heart failure may be non-cardiomyocytes, but the paper does not directly compare JQ1-associated transcriptional changes in cardiomyocytes with those in other cardiac cell populations. (LLM, conf=0.83)
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Self-citationBETs that cover the spread from acquired to heritable heart failure
Alexanian, M., & Haldar, S. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci140304 · Cited by 2 · see citing works
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BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection
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Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart
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BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression
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Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases
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The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy
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Cold shock domain–containing protein E1 is a posttranscriptional regulator of the LDL receptor
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A genome-wide CRISPR screen identifies BRD4 as a regulator of cardiomyocyte differentiation
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Self-citationBromodomain‐containing protein 4 and its role in cardiovascular diseases
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Self-citationBET Protein-Mediated Transcriptional Regulation in Heart Failure
Ijaz, T., & Burke, M. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116059 · Cited by 14 · see citing works
Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure PathogenesisPreprint
Alexanian, M., Padmanabhan, A., Nishino, T., Travers, J. G., Ye, L., Lee, C. Y., Sadagopan, N., Huang, Y., Pelonero, A., Auclair, K., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.06.522937 · Cited by 14 · see citing works
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The role of metabolism in directed differentiation versus trans-differentiation of cardiomyocytes
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Rubio‐Tomás, T., Soler‐Botija, C., Martínez-Estrada, O. M., & Villena, J. A. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116185 · Cited by 12 · see citing works
Histone Deacetylase 6 Inhibitor JS28 Prevents Pathological Gene Expression in Cardiac Myocytes
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Role of transcriptional cofactors in cardiovascular diseases
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Roles of Brd4 in Vascular Smooth Muscle Cells: Implications for Aging and Vascular Dysfunction
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Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases
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A Minireview on BET Inhibitors: Beyond Bromodomain Targeting
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Epigenetics of Mitochondria-Associated Genes in Striated Muscle
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Cardiac epigenome in heart development and disease
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Organoids in COVID-19: can we break the glass ceiling?
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Discovery of drugs to treat cytokine storm-induced cardiac dysfunction using human cardiac organoidsPreprint
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Novel Techniques, Biomarkers and Molecular Targets to Address Cardiometabolic Diseases
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BETs that cover the spread from acquired to heritable heart failure
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Self-citationBET inhibitors in cardiovascular diseases: from atherosclerosis to heart failure
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Endodermal BRD4 mediates epithelial-mesenchymal crosstalk during lung developmentPreprint
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Taking BETs on cardiomyocyte differentiation
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BRD4 promotes endodermal cell fate during mammalian lung development
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Epigenetic remodeling mechanisms in heart failure and their pathological significance
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Haploinsufficiency of brd4 causes adult-onset cardiac arrhythmia and cardiomyopathy in zebrafishPreprint
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Cell Type-Specific Roles for BRD4 in Heart Failure
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- Authors
- Padmanabhan, A., Alexanian, M., Linares-Saldana, R., González-Terán, B., Andreoletti, G., Huang, Y., Connolly, A. J., Kim, W., Hsu, A., Duan, Q., Winchester, S. A. B., Felix, F., Perez-Bermejo, J. A., Wang, Q., Li, L., Shah, P. P., Haldar, S. M., Jain, R., & Srivastava, D.
- Affiliations
- Gladstone Institutes (US)
- University of Pennsylvania Health System (US)
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA (A.P., M.A., B.G.-T., Y.H., A.H., Q.D., S.A.B.W., F.F., J.A.P.-B., S.M.H., D.S.).
- University of California, San Francisco (US)
- Corresponding author
- Padmanabhan, Arun
- Alexanian, Michael
- Linares-Saldana, Ricardo
- Jain, Rajan
- Srivastava, Deepak
- ORCID
- Venue
- Circulation
- Published
- 2020-12-15
- Volume
- 142
- Issue
- 24
- Pages
- 2338-2355
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC7736290
- OpenAlex
- W3093674907
- Cited by
- 60
- References
- 81
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 10 · 2023: 8 · 2022: 10 · 2021: 8 · 2020: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation (1548571)
- American Heart Association
- A.P. Giannini Foundation
- Tobacco-Related Disease Research Program
- Gilead Sciences
- University of Pennsylvania
- Gladstone Institutes
- Giannini Foundation of Agricultural Economics
- Roddenberry Foundation
- Sarnoff Cardiovascular Research Foundation
- Gilead Research Scholars
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186704)
- National Institutes of Health (1c06rr018928-01)
- National Heart, Lung, and Blood Institute (R01HL139783, P01HL146366, P01HL089707, R01HL127240, F31HL147416, R01HL057181)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- BRD4, GATA4, bromodomain proteins, BET proteins, cardiomyocytes, mitochondrial homeostasis, myocardial metabolism, PPARγ coactivator, PGC-1α, PPARGC1B, tissue-specific gene regulation, cardiac contractile function, heart failure
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Bromodomain Containing Proteins, Animals, Energy Metabolism, Gene Expression Regulation, Genotype, Homeostasis, Humans, Mice, Inbred C57BL, Mitochondria, Heart, Nuclear Proteins, Phenotype, Protein Binding, Transcription Factors, Ventricular Function, Left, Rats, Sprague-Dawley, Mice, Knockout, Ventricular Dysfunction, Left, Gene Expression Profiling, Myocytes, Cardiac, GATA4 Transcription Factor, HEK293 Cells, Transcriptome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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