Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development

Maitra, Meenakshi; Schluterman, Marie K.; Nichols, Haley A.; Richardson, James A.; Lo, Cecilia W.; Srivastava, Deepak; Garg, Vidu

doi:10.1016/j.ydbio.2008.11.004

Cited by 174 publications

(160 citation statements)

References 47 publications

(66 reference statements)

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“…7,20,21,27,28 A disrupted interaction between GATA4 and TBX5 is involved in ASDs in both humans and mice. 4,19 Similarly, a link between GATA6 and TBX5 has been recognized, and compound heterozygosity of both genes results in defects in myocardial development. 19 Although no direct interactions have been reported between GATA6 TAD region and other transcriptional factors, such as GATA4 and TBX5, the general interactions between those transcriptional factors may aid in our understanding of the mechanistic basis of ASD because of GATA6 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…7 Recent experiments in animals have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, highlighting the potential involvement of GATA6 mutations in the pathogenesis of human CHD. [18][19][20][21] Although mutations in GATA6 have recently been related to patients with persistent truncus arteriosus, their involvement in, and impact on, various types of CHD are unclear. 22 To explore this question, we investigated 270 individuals with sporadic CHD for GATA6 mutations and identified the biological functional deficits of an identified mutation in vitro.…”

Section: Introductionmentioning

confidence: 99%

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A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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“…A network of genes encoding multiple cardiogenic transcription factors are coordinately expressed as a sequence of processes leading to the fully developed functional mammalian heart: the ordered formation of the cardiac tube, the looping to form the atrial and ventricular chambers of the left heart, followed by the formation of the atrial and ventricular chambers of the right heart together with the specialized conducting system of the interventricular septum and the aortic outflow tract (Lyons et al, 1995;Liang et al, 2001;Nishida et al, 2002;Garg et al, 2003;Watt et al, 2004;Niu et al, 2008;Maitra et al, 2009). The key transcription factors essential to the function of this network include the homeodomain protein Nkx-2.5 and the cysteine zinc finger protein GATA4, representatives of larger protein families playing additional roles in general development.…”

Section: Introductionmentioning

confidence: 99%

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Chen

Singh

et al. 2012

Journal of Cell Science

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SummaryCardiac development requires interplay between the regulation of gene expression and the assembly of functional sarcomeric proteins. We report that UNC-45b recessive loss-of-function mutations in C3H and C57BL/6 inbred mouse strains cause arrest of cardiac morphogenesis at the formation of right heart structures and failure of contractile function. Wild-type C3H and C57BL/6 embryos at the same stage, E9.5, form actively contracting right and left atria and ventricles. The known interactions of UNC-45b as a molecular chaperone are consistent with diminished accumulation of the sarcomeric myosins, but not their mRNAs, and the resulting decreased contraction of homozygous mutant embryonic hearts. The novel finding that GATA4 accumulation is similarly decreased at the protein but not mRNA levels is also consistent with the function of UNC-45b as a chaperone. The mRNAs of known downstream targets of GATA4 during secondary cardiac field development, the cardiogenic factors Hand1, Hand2 and Nkx-2.5, are also decreased, consistent with the reduced GATA4 protein accumulation. Direct binding studies show that the UNC-45b chaperone forms physical complexes with both the alpha and beta cardiac myosins and the cardiogenic transcription factor GATA4. Co-expression of UNC-45b with GATA4 led to enhanced transcription from GATA promoters in naïve cells. These novel results suggest that the heart-specific UNC-45b isoform functions as a molecular chaperone mediating contractile function of the sarcomere and gene expression in cardiac development.

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“…T-box genes encode transcription factors involved in the regulation of developmental processes, cell-cell signaling, negative regulation of cardiac muscle cell proliferation, induction of apoptosis and negative regulation of cell migration (He et al, 2002;Mori et al, 2006;Plageman and Yutzey, 2006;Maitra et al, 2009). This gene is located on human chromosome 12q24.1.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

Cheung

et al. 2010

Oncogene

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T-box transcription factor 5 (TBX5) is a member of a phylogenetically conserved family of genes involved in the regulation of developmental processes. The function of TBX5 in cancer development is largely unclear. We identified that TBX5 was preferentially methylated in cancer using methylation-sensitive arbitrarily primed PCR. We aim to clarify the epigenetic inactivation, biological function and clinical significance of TBX5 in colon cancer. Promoter methylation was evaluated by combined bisulfite restriction analysis and bisulfite genomic sequencing. Cell proliferation was examined by cell viability assay and colony formation assay, apoptosis by flow cytometry and cell migration by wound-healing assay. TBX5 target genes were identified by cDNA microarray analysis. Cox regression model and log-rank test were used to identify independent predictors of prognosis. TBX5 was silenced or downregulated in 88% (7/8) colon cancer cell lines, but was expressed in normal colon tissues. Loss of gene expression was associated with promoter methylation. The biological function of TBX5 in human colon cancer cells was examined. Re-expression of TBX5 in silenced colon cancer cell lines suppressed colony formation (Po0.001), proliferation (Po0.001), migration and induced apoptosis (Po0.01). Induction of apoptosis was mediated through cross-talk of extrinsic apoptosis pathway, apoptotic BCL2-associated X protein and Granzyme A signaling cascades. TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. TBX5 methylation was detected in 68% (71/105) of primary colon tumors. Multivariate analysis showed that patients with TBX5 methylation had a significantly poor overall survival (P ¼ 0.0007). In conclusion, we identified a novel functional tumor suppressor gene TBX5 inactivated by promoter methylation in colon cancer. Detection of methylated TBX5 may serve as a potential biomarker for the prognosis of this malignancy.

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Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development

Cited by 174 publications

References 47 publications

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer

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