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Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis [ATAC-Seq]

ABSTRACT: Heterozygous mutations in GATA4 cause congenital heart defects and cardiomyopathy through unknown mechanisms. To gain insights into the open chromatin status during human cardiac development due to GATA4 heterozygosity, we performed ATAC-seq of wildtype and GATA4-G296S diseased cardiac progenitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85630 | GEO | 2016/12/15

SECONDARY ACCESSION(S): PRJNA339029

REPOSITORIES: GEO

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Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis [RNA-Seq]

Project description:Heterozygous mutations in GATA4 cause congenital heart defects and cardiomyopathy through unknown mechanisms. To gain insights into the trancriptome perturbations during human cardiac development due to GATA4 heterozygosity, we performed RNA-seq of isogenic wildtype and GATA4-G296S diseased cardiac progenitors (CPCs) and cardiomyocytes (CMs).

2016-12-15 | GSE85623 | GEO

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis [ChIP-Seq]

Project description:Heterozygous mutations in GATA4 cause congenital heart defects and cardiomyopathy through unknown mechanisms. To gain insights into the genome-wide localization perturbations during human cardiac development due to GATA4 heterozygosity, we performed ChIP-seq of wildtype and GATA4-G296S diseased cardiomyocytes.

2016-12-15 | GSE85628 | GEO

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

Project description: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.

| S-EPMC5180611 | biostudies-literature

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

Project description:Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

| PRJNA338963 | ENA

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-12-15 | GSE85631 | GEO

Transcription profiling of hearts from mice heterozygous for Gata4 mutation (G4D) to investigate the significance of Gata4 in regulating postnatal heart function and in regulating the hypertrophic response of the heart to pathological stress.

Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.

2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress

Genome-wide occupancy profile of Tbx3, Gata4, Nkx2-5 and p300 in adult mouse whole heart

Project description:The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Examination of 3 cardiac transcription factors and p300 in adult mouse heart

2012-06-22 | E-GEOD-35151 | biostudies-arrayexpress

Expression data from mouse heart with and without GATA4 S105A mutation; with and without adrenergic stress

2011-06-30 | GSE30314 | GEO

Transcription profiling of mouse Tie2-Cre transgene endothelial cells with inactivated Gata4 reveals development of heart valves requires Gata4 expression in endothelial-derived cells

Project description:Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in formation of portions of the atrial and ventricular septae, and generation of thin, pliable valves. The transcription factor Gata4 is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling. Experiment Overall Design: To further investigate the role of Gata4 in EC development, we specifically inactivated Gata4 in endothelium and endothelium-derived cushion mesenchyme. All mice were maintained in a mixed C57BL6/129 genetic background. Gata4wt/flox; T2Cre+ mice were crossed with Gata4flox/flox mice to yield Gata4flox/flox (CONTROL); T2Cre+ (Gata4T2del) (MUTANT) mice.

2008-06-13 | E-GEOD-5298 | biostudies-arrayexpress

Expression data from mouse heart with and without GATA4 S105A mutation; with and without adrenergic stress

Project description:Serine 105 phosphorylation of GATA4 is necessary for stress-induced cardiac hypertrophy in vivo. We used microarrays to detail global gene expression program alterations that arise in response to the ablation of the Gata4 S105 phosphorylation site in basal and adrenergic-stressed heart ventricles. Wildtype and genetically engineered mice were subjected to control or pseudoephedrine treatment and heart ventricle RNAs were extracted and hybridized on Affymetrix microarrays. Comparisons consisted of identifying treatment- and genotype-affected gene expression patterns.

2011-06-30 | E-GEOD-30314 | biostudies-arrayexpress

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