Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85623 | GEO | 2016/12/15
SECONDARY ACCESSION(S): PRJNA339027
REPOSITORIES: GEO
Similar Datasets
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
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
Project description:Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGFbeta) inhibition efficiently promotes reprogramming. However, the mechanisms by which TGFbeta; blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3), demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGFbeta; signaling regulates the interaction between GATA4 and JMJD3. TGF-beta; activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) exhibits reduced binding to JMJD3 and impaired cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGFbeta; pathway activation impairs cardiac gene programming by interfering with GATA4-JMJD3 interactions.
2021-02-13 | GSE145290 | GEO
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
Project description:Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis
| PRJNA338963 | ENA
Project description:Cardiac hypertrophy is regulated by the zinc finger-containing DNA binding factors Gata4 and Gata6, both of which are required to mount a productive growth response of the adult heart. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response. We determined that Gata4 and Gata6 play a redundant and dosage-sensitive role in programming the hypertrophic growth response itself following pressure overload stimulation. However, non-redundant functions were identified as functional decompensation induced by either Gata4 or Gata6 deletion was not rescued by the reciprocal transgene, and only Gata4 heart-specific deletion produced a reduction in capillary density after pressure overload. Gene expression profiling from hearts of these gene-deleted mice showed both overlapping and unique transcriptional codes, with Gata4 exhibiting the strongest impact. These results indicate that Gata4 and Gata6 play a dosage-dependent and semi-redundant role in programming cardiac hypertrophy, but that each has a unique role in maintaining cardiac homeostasis and adaptation to injury that cannot be compensated by the other. Microarray-bassed gene expression profiling identified overlapping, distinct, and quantitatively/differentially regulated classes of Gata4 or Gata6 regulated genes. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles in programming cardiac hypertrophic responses and adaptation to stress or injury, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response.
2014-01-01 | E-GEOD-52317 | biostudies-arrayexpress
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
Project description:Rationale: Cardiogenesis is regulated by a complex interplay between transcription factors and chromatin-modifying enzymes. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor-binding site analysis on upstream promoter regions of genes that are enriched in ES cell-derived CPCs. From 32 candidate transcription factors screened, we found that YY1, a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1 kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays and in vivo chromatin immunoprecipitation (ChIP) and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with GATA4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by ES cell-based assays where we show that the over-expression of YY1 enhanced the cardiogenic differentiation ES cells into CPCs in a cell autonomous manner. Conclusion: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. We report the identification of putative YY1 target genes in cardiac progenitor cells (CPCs). Two samples of independently FACS-purified eGFP+ CPCs were examined against the input.
2013-06-01 | E-GEOD-35370 | biostudies-arrayexpress
Project description:The Gata4 transcription factor is essential for normal heart development, but the molecular basis for its function remain poorly understood. We profiled at the whole genome level transcript changes in cardiomyocytes when Gata4 is depleted from zebrafish embryos. Our objective was to elucidate the cardiomyocyte-specific molecular program functioning downstream of Gata4 in order to better understand the role of Gata4 in cardiac morphogenesis. Six samples in total are deposited. Three replicate control samples and three replicate Gata4 morphant samples were analyzed.
2014-02-06 | E-GEOD-44233 | biostudies-arrayexpress
Project description:The transcriptional profiles of cardiac cells derived from murine embryos and from mouse embryonic stem cells (mESCs) have primarily been studied within a cell population. However, the characterization of gene expression in these cells at a single cell level may demonstrate unique variations that are not able to be appreciated as a pool. In this study, we aimed to establish a single cell quantitative PCR platform and perform side-by-side comparison between cardiac progenitors cells (CPCs) and cardiomyocytes (CMs) derived from mESC and mouse embryos. We first generated a reference map for cardiovascular single cells through quantifying lineage-defining genes for CPCs, CMs, smooth muscle cells (SMCs), endothelial cells (EDCs), fibroblasts, and mESCs. This panel was then applied against day 10.5 embryonic heart single cells to demonstrate its ability to identify each endocardial cell and chamber-specific CM. In addition, we compared the gene expression profile of embryo- and mESC-derived CPCs and CMs at different developmental stages and showed that mESC-derived CM is phenotypically similar to embryo-derived CM up to the neonatal stage. Furthermore, we show that single cell expression assay coupled with time-lapse microscopy can resolve the identity and the lineage relationships between progenies of single cultured CPC. With this approach, we found differential propensity for mESC-derived CPCs to become SMCs or CMs, whereas single embryo-derived CPC to become either EDCs or CMs. These results demonstrate that multiplex gene expression analysis in single cells is a powerful tool in examining the unique behavior in individual embryo- or mESC-derived cardiac cells.
2015-01-16 | GSE64938 | GEO