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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85628 | GEO | 2016/12/15

SECONDARY ACCESSION(S): PRJNA339028

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 [ATAC-Seq]

Project description: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.

2016-12-15 | GSE85630 | 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

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

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

2012-06-22 | GSE35151 | GEO

Transcription profiling of Xenopus animal cap cardiogenesis model to examine immediate early targets of Gata4 and Gata5.

Project description:Gata factors are amongst the genes expressed early on in the process of cardiogenesis. We used microarrays to examine the immediate early targets of Gata4 and Gata5 in the Xenopus leavis animal cap cardiogenesis model. We hope to use these data to examine the roles of Gata4 and Gata5 in cardiogenesis and also to begin to dissect out the common and distinct targets of Gata4 and Gata5. Experiment Overall Design: Xenopus leavis embryos were injected at the one cell stage with dexamethasone-inducible Gata4 or Gata5 mRNA constructs (to examine endodermal and mesodermal targets) or with Gata4 in the presence of Dkk1 (to examine mesodermal targets.) Embryos were cultured to stage 9, whereupon animal caps were excised and cultured for 2.5 hours in media containing dexamethasone to induce the constructs and cycloheximide to block de novo protein synthesis and thus give only immediate early targets.

2008-10-18 | E-GEOD-8496 | biostudies-arrayexpress

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

Cyclin D2 is a GATA4 cofactor in cardiogenesis.

Project description:The G1 cyclins play a pivotal role in regulation of cell differentiation and proliferation. The mechanisms underlying their cell-specific roles are incompletely understood. Here, we show that a G1 cyclin, cyclin D2 (CycD2), enhances the activity of transcription factor GATA4, a key regulator of cardiomyocyte growth and differentiation. GATA4 recruits CycD2 to its target promoters, and their interaction results in synergistic activation of GATA-dependent transcription. This effect is specific to CycD2 because CycD1 is unable to potentiate activity of GATA4 and is CDK-independent. GATA4 physically interacts with CycD2 through a discreet N-terminal activation domain that is essential for the cardiogenic activity of GATA4. Human mutations in this domain that are linked to congenital heart disease interfere with CycD2-GATA4 synergy. Cardiogenesis assays in Xenopus embryos indicate that CycD2 enhances the cardiogenic function of GATA4. Together, our data uncover a role for CycD2 as a cardiogenic coactivator of GATA4 and suggest a paradigm for cell-specific effects of cyclin Ds.

| S-EPMC3910654 | biostudies-literature

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