Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis
Open accessAbstract
Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.
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Direct GATA4 targets (as defined by ChIP-seq) were significantly more impacted by in silico deletion of GATA4 in fetal cardiomyocytes compared to indirect targets.
“Notably, direct GATA4 targets (as defined by ChIP-seq33) were significantly more impacted by in silico deletion of GATA4 in fetal cardiomyocytes compared to indirect targets (Fig. 5a).”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [33]
In silico deletion of GATA4 had a significantly higher effect on genes known to be most significantly dysregulated by GATA4 variants in a previously reported iPSC disease model of GATA4-related heart defects.
“In silico deletion of GATA4 had a significantly higher effect on genes known to be most significantly dysregulated by GATA4 variants in a previously reported iPSC disease model of GATA4-related heart defects33 (Extended Data Fig. 9e).”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [33]
In silico deletion of GATA4 or TBX5 alone had a significantly more deleterious effect on their known co-bound targets compared to housekeeping genes.
“Indeed, in silico deletion of GATA4 or TBX5 alone had a significantly more deleterious effect on their known co-bound targets33 compared to housekeeping genes.”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [33]
In silico deletion of GATA4 was significantly more deleterious to previously reported highest confidence GATA4 targets than to housekeeping genes.
“In silico deletion of GATA4 was significantly more deleterious to the previously reported highest confidence GATA4 targets33 than to housekeeping genes.”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [33]
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- Authors
- Ang, Y.-S., Rivas, R. N., Ribeiro, A. J. S., Srivas, R., Rivera, J., Stone, N. R., Pratt, K., Mohamed, T. M. A., Fu, J.-D., Spencer, C. I., Tippens, N. D., Li, M., Narasimha, A., Radzinsky, E., Moon-Grady, A. J., Yu, H., Pruitt, B. L., Snyder, M. P., & Srivastava, D.
- Affiliations
- Gladstone Institutes (US)
- Stanford University (US)
- Stanford Medicine (US)
- Cornell University (US)
- Corresponding author
- Srivastava, Deepak
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 167
- Issue
- 7
- Pages
- 1734-1749.e22
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5180611
- OpenAlex
- W2560905785
- Cited by
- 294
- References
- 4
- Citations by year
- 2026: 21 · 2025: 58 · 2024: 30 · 2023: 22 · 2022: 29 · 2021: 32 · 2020: 27 · 2019: 28 · 2018: 27 · 2017: 19 · 2016: 1
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- American Heart Association (14POST18360018)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/S01302/1)
- National Institutes of Health (7r21hl130993-03, 1c06rr018928-01)
- National Heart, Lung, and Blood Institute (U01HL100406, R21 HL130993, UM1HL098179, P01HL089707, R01HL122887, U01HL098179, R01HL057181)
- National Human Genome Research Institute (T32HG000044)
- National Institute of General Medical Sciences (T32GM007618)
- National Institute of Biomedical Imaging and Bioengineering (R01EB006745)
- National Center for Research Resources (C06-RR-018928)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- GATA4, missense mutations, TBX5, transcription factor cooperativity, cardiac septal defects, cardiomyopathy, iPSC-derived cardiomyocytes, cardiac enhancers, chromatin accessibility, open chromatin, calcium handling, cardiomyocyte contractility, heart development, transcriptional repression
- MeSH terms
- Chromatin, Enhancer Elements, Genetic, Female, Heart, Heart Defects, Congenital, Humans, Male, Signal Transduction, Phosphatidylinositol 3-Kinases, Mutation, Missense, T-Box Domain Proteins, Myocytes, Cardiac, GATA4 Transcription Factor, Induced Pluripotent Stem Cells
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