Journal articles: 'Gata6'

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Capo-chichi, Callinice D., Jennifer L. Smedberg, Malgorzata Rula, Emmanuelle Nicolas, Anthony T. Yeung, Richard F. Adamo, Andrey Frolov, Andrew K. Godwin, and Xiang-Xi Xu. "Alteration of Differentiation Potentials by Modulating GATA Transcription Factors in Murine Embryonic Stem Cells." Stem Cells International 2010 (2010): 1–15. http://dx.doi.org/10.4061/2010/602068.

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Background. Mouse embryonic stem (ES) cells can be differentiated in vitro by aggregation and/or retinoic acid (RA) treatment. The principal differentiation lineage in vitro is extraembryonic primitive endoderm. Dab2, Laminin, GATA4, GATA5, and GATA6 are expressed in embryonic primitive endoderm and play critical roles in its lineage commitment.Results. We found that in the absence of GATA4 or GATA5, RA-induced primitive endoderm differentiation of ES cells was reduced. GATA4 (−/−) ES cells express higher level of GATA5, GATA6, and hepatocyte nuclear factor 4 alpha marker of visceral endoderm lineage. GATA5 (−/−) ES cells express higher level of alpha fetoprotein marker of early liver development. GATA6 (−/−) ES cells express higher level of GATA5 as well as mesoderm and cardiomyocyte markers which are collagen III alpha-1 and tropomyosin1 alpha. Thus, deletion of GATA6 precluded endoderm differentiation but promoted mesoderm lineages.Conclusions. GATA4, GATA5, and GATA6 each convey a unique gene expression pattern and influences ES cell differentiation. We showed that ES cells can be directed to avoid differentiating into primitive endoderm and to adopt unique lineages in vitro by modulating GATA factors. The finding offers a potential approach to produce desirable cell types from ES cells, useful for regenerative cell therapy.

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Yu, Min, Ulrica Wang, and Zhengxin Wang. "E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells." Biochemical Journal 473, no. 15 (July 28, 2016): 2331–43. http://dx.doi.org/10.1042/bcj20160130.

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WDR77 (WD repeat domain 77) is expressed during earlier lung development when cells are rapidly proliferating, but is absent from adult lung. It is re-activated during lung tumorigenesis and is essential for lung cancer cell proliferation. Signalling pathways/molecules that control WDR77 gene expression are unknown. Promoter mapping, gel shift assay and ChIP revealed that the WDR77 promoter contains bona fide response elements for E2F and GATA transcriptional factors as demonstrated in prostate cancer, lung cancer and erythroid cells, as well as in mouse lung tissues. The WDR77 promoter is transactivated by E2F1, E2F3, GATA1 and GATA6, but suppressed by E2F6, GATA1 and GATA3 in prostate cancer PC3 cells. WDR77 expression is associated with E2F1, E2F3, GATA2 and GATA6 occupancy on the WDR77 gene, whereas, in contrast, E2F6, GATA1 and GATA3 occupancy is associated with the loss of WDR77 expression during erythroid maturation and lung development. More importantly, the loss of WDR77 expression that results from E2F and GATA switches is required for cellular differentiation of erythroid and lung epithelial cells. In contrast, lung cancer cells avoid post-mitotic differentiation by sustaining WDR77 expression. Altogether, the present study provides a novel molecular mechanism by which WDR77 is regulated during erythroid and lung development and lung tumorigenesis.

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Engels, Manon, Paul N. Span, Rod T. Mitchell, Joop J. T. M. Heuvel, Monica A. Marijnissen-van Zanten, Antonius E. van Herwaarden, Christina A. Hulsbergen-van de Kaa, et al. "GATA transcription factors in testicular adrenal rest tumours." Endocrine Connections 6, no. 8 (November 2017): 866–75. http://dx.doi.org/10.1530/ec-17-0215.

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Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n = 16), Leydig cell tumours (LCTs; n = 7), adrenal (foetal (n = 6) + adult (n = 10)) and testis (foetal (n = 13) + adult (n = 8)). We found testis-like GATA4, and adrenal-like GATA3 and GATA6 gene expressions by qPCR in human TARTs, indicating mixed testicular and adrenal characteristics of TARTs. Currently, no marker is available to discriminate TARTs from LCTs, leading to misdiagnosis and incorrect treatment. GATA3 and GATA6 mRNAs exhibited excellent discriminative power (area under the curve of 0.908 and 0.816, respectively), while immunohistochemistry did not. GATA genes contain several CREB-binding sites and incubation with 0.1 mM dibutyryl cAMP for 4 h stimulated GATA3, GATA4 and GATA6 expressions in a human foetal testis cell line (hs181.tes). Incubation of adrenocortical cells (H295RA) with ACTH, however, did not induce GATA expression in vitro. Although ACTH did not dysregulate GATA expression in the only human ACTH-sensitive in vitro model available, our results do suggest that aberrant expression of GATA transcription factors in human TARTs might be involved in TART formation.

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Zhao, Roong, Alistair J. Watt, Jixuan Li, Jennifer Luebke-Wheeler, Edward E. Morrisey, and Stephen A. Duncan. "GATA6 Is Essential for Embryonic Development of the Liver but Dispensable for Early Heart Formation." Molecular and Cellular Biology 25, no. 7 (April 1, 2005): 2622–31. http://dx.doi.org/10.1128/mcb.25.7.2622-2631.2005.

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ABSTRACT Several lines of evidence suggest that GATA6 has an integral role in controlling development of the mammalian liver. Unfortunately, this proposal has been impossible to address directly because mouse embryos lacking GATA6 die during gastrulation. Here we show that the early embryonic deficiency associated with GATA6-knockout mice can be overcome by providing GATA6-null embryos with a wild-type extraembryonic endoderm with the use of tetraploid embryo complementation. Analysis of rescued Gata6 − / − embryos revealed that, although hepatic specification occurs normally, the specified cells fail to differentiate and the liver bud does not expand. Although GATA6 is expressed in multiple tissues that impact development of the liver, including the heart, septum transversum mesenchyme, and vasculature, all are relatively unaffected by loss of GATA6, which is consistent with a cell-autonomous requirement for GATA6 during hepatogenesis. We also demonstrate that a closely related GATA factor, GATA4, is expressed transiently in the prehepatic endoderm during hepatic specification and then lost during expansion of the hepatic primordium. Our data support the proposal that GATA4 and GATA6 are functionally redundant during hepatic specification but that GATA6 alone is available for liver bud growth and commitment of the endoderm to a hepatic cell fate.

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Sartori, Daniel J., Christopher J. Wilbur, Simon Y. Long, Matthew M. Rankin, Changhong Li, Jonathan P. Bradfield, Hakon Hakonarson, Struan F. A. Grant, William T. Pu, and Jake A. Kushner. "GATA Factors Promote ER Integrity and β-Cell Survival and Contribute to Type 1 Diabetes Risk." Molecular Endocrinology 28, no. 1 (January 1, 2014): 28–39. http://dx.doi.org/10.1210/me.2013-1265.

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Abstract Pancreatic β-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult β-cells remains undefined. To investigate the role of GATA factors in adult β-cells, we derived β-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. β-Cell Gata4 deletion modestly increased the proportion of dying β-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in β-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored β-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such β-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and β-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.

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Hui, Yvonne Y., and Holly A. LaVoie. "GATA4 Reduction Enhances 3′,5′-Cyclic Adenosine 5′-Monophosphate-Stimulated Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid and Progesterone Production in Luteinized Porcine Granulosa Cells." Endocrinology 149, no. 11 (July 24, 2008): 5557–67. http://dx.doi.org/10.1210/en.2008-0484.

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Previous studies with cultured granulosa cells implicated GATA4 in gonadotropin regulation of the steroidogenic acute regulatory protein (STAR) gene. Caveats to these prior studies exist. First, GATA4 levels are reduced in granulosa-luteal cells after the LH surge when GATA6 expression is relatively high. Second, STAR mRNA expression is negligible in granulosa cells until after the LH surge. Both exogenous GATA4 and GATA6 can transactivate STAR gene promoter constructs. We used an RNA interference (RNAi) approach to determine the contributions of GATA4 and GATA6 to cAMP analog regulation of the endogenous STAR gene in luteinizing granulosa cells. STAR mRNA was stimulated by cAMP under control RNAi conditions. Surprisingly, GATA4 reduction by its respective RNAi approximately doubled the cAMP induction of STAR mRNA. At 24 h cAMP treatment, this augmentation was abolished by co-down-regulation of GATA4+GATA6. GATA6 down-regulation by itself did not alter STAR mRNA levels. GATA4+GATA6 co-down-regulation elevated basal CYP11A mRNA at 24 h treatment but did not affect its induction by cAMP. Basal levels of HSD3B mRNA were reduced by GATA4 RNAi conditions leading to a greater fold induction of its mRNA by cAMP. Fold cAMP-stimulated progesterone production was enhanced by GATA4 down-regulation but not by GATA4+GATA6 co-down-regulation. These data implicate GATA6 as the facilitator in cAMP-stimulated STAR mRNA and downstream progesterone accumulation under reduced GATA4 conditions. Data also demonstrate that basal levels of GATA4/6 are not required for cAMP induction of the STAR gene. The altered ratio of GATA4 to GATA6 after ovulation may allow GATA6 to enhance STAR mRNA accumulation.

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Sumi, Koichi, Toshiya Tanaka, Aoi Uchida, Kenta Magoori, Yasuyo Urashima, Riuko Ohashi, Hiroto Ohguchi, et al. "Cooperative Interaction between Hepatocyte Nuclear Factor 4α and GATA Transcription Factors Regulates ATP-Binding Cassette Sterol Transporters ABCG5 and ABCG8." Molecular and Cellular Biology 27, no. 12 (April 2, 2007): 4248–60. http://dx.doi.org/10.1128/mcb.01894-06.

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ABSTRACT Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4α (HNF4α) in the ABCG5/ABCG8 intergenic promoter, through which HNF4α strongly activated the expression of a reporter gene in both directions. The HNF4α-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4α. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4α leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4α and GATA were essential for maximal synergism. We also show that HNF4α, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4α and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4α acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.

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Rath, Nibedita, Zhishan Wang, Min Min Lu, and Edward E. Morrisey. "LMCD1/Dyxin Is a Novel Transcriptional Cofactor That Restricts GATA6 Function by Inhibiting DNA Binding." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 8864–73. http://dx.doi.org/10.1128/mcb.25.20.8864-8873.2005.

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ABSTRACT The activity of GATA factors is regulated, in part, at the level of protein-protein interactions. LIM domain proteins, first defined by the zinc finger motifs found in the Lin11, Isl-1, and Mec-3 proteins, act as coactivators of GATA function in both hematopoietic and cardiovascular tissues. We have identified a novel GATA-LIM interaction between GATA6 and LMCD1/dyxin. The LIM domains and cysteine-rich domains in LMCD1/dyxin and the carboxy-terminal zinc finger of GATA6 mediate this interaction. Expression of LMCD1/dyxin is remarkably similar to that of GATA6, with high-level expression observed in distal airway epithelium of the lung, vascular smooth muscle, and myocardium. In contrast to other GATA-LIM protein interactions, LMCD1/dyxin represses GATA6 activation of both lung and cardiac tissue-specific promoters. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that LMCD1/dyxin represses GATA6 function by inhibiting GATA6 DNA binding. These data reveal an interaction between GATA6 and LMCD1/dyxin and demonstrate a novel mechanism through which LIM proteins can assert their role as transcriptional cofactors of GATA proteins.

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Laforest, Brigitte, and Mona Nemer. "GATA5 interacts with GATA4 and GATA6 in outflow tract development." Developmental Biology 358, no. 2 (October 2011): 368–78. http://dx.doi.org/10.1016/j.ydbio.2011.07.037.

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Yang, Honghua, Min Min Lu, Lili Zhang, Jeffrey A. Whitsett, and Edward E. Morrisey. "GATA6 regulates differentiation of distal lung epithelium." Development 129, no. 9 (May 1, 2002): 2233–46. http://dx.doi.org/10.1242/dev.129.9.2233.

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GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal epithelium of the lung during development. To define the role that GATA6 plays during lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal lung epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.

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Qu, Xiaolu, Leyan Yan, Rihong Guo, Hui Li, and Zhendan Shi. "ROS-Induced GATA4 and GATA6 Downregulation Inhibits StAR Expression in LPS-Treated Porcine Granulosa-Lutein Cells." Oxidative Medicine and Cellular Longevity 2019 (April 22, 2019): 1–14. http://dx.doi.org/10.1155/2019/5432792.

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LPS is a major endotoxin produced by gram-negative bacteria, and exposure to it commonly occurs in animal husbandry. Previous studies have shown that LPS infection disturbs steroidogenesis, including progesterone production, and subsequently decreases animal reproductive performance. However, little information about the underlying mechanisms is available thus far. In the present study, an in vitro-luteinized porcine granulosa cell model was used to study the underlying molecular mechanisms of LPS treatment. We found that LPS significantly inhibits progesterone production and downregulates the expressions of progesterone synthesis-associated genes (StAR, CYP11A1, and 3β-HSD). Furthermore, the levels of ROS were significantly increased in an LPS dose-dependent manner. Moreover, transcriptional factors GATA4 and GATA6, but not NR5A1, were significantly downregulated. Elimination of LPS-stimulated ROS by melatonin or vitamin C could restore the expressions of GATA4, GATA6, and StAR. In parallel, StAR expression was also inhibited by the knockdown of GATA4 and GATA6. Based on these data, we conclude that LPS impairs StAR expression via the ROS-induced downregulation of GATA4 and GATA6. Collectively, these findings provide new insights into the understanding of reproductive losses in animals suffering from bacterial infection and LPS exposure.

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Pavlov, Kirill, Judith Honing, Coby Meijer, Wytske Boersma-van Ek, Frans Peters, Anke van den Berg, Arend Karrenbeld, John Theodorus Plukker, Frank Kruyt, and Jan Kleibeuker. "GATA6 expression in Barrett’s metaplasia development and malignant progression." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 26. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.26.

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26 Background: Barrett’s metaplasia is characterized by the presence of a columnar metaplastic epithelium in the esophagus. Barrett’s metaplasia can show malignant progression towards esophageal adenocarcinoma by a metaplasia-dysplasia-carcinoma sequence. The underlying mechanisms of Barrett’s metaplasia development and malignant progression are poorly understood. The transcription factor GATA-6 is known to be involved in columnar differentiation and carcinogenesis. GATA6 gene amplification was recently linked with aggressiveness in esophageal adenocarcinoma. Here, we studied GATA6 protein expression in normal squamous, metaplastic, dysplastic and esophageal adenocarcinoma tissues in order to identify a possible role of GATA-6 in the development and malignant progression of Barrett’s metaplasia. Methods: Samples of squamous epithelium (N=37), Barrett’s non-intestinal metaplasia (N=16), Barrett’s intestinal metaplasia (N=29), high-grade dysplasia (N= 39), in situ esophageal adenocarcinoma (N=29) and an esophageal adenocarcinoma tissue microarray (N=95) were stained with a polyclonal antibody against GATA6. Staining intensity was categorized as absent, weak, normal or strong. Scoring was performed by two independent observers and validated by a pathologist. Results: GATA6 expression was absent in squamous epithelium but expressed in all samples of Barrett’s metaplasia, preferentially in the lower half of the crypt. Expansion of GATA6-positive cells throughout the crypt was observed in high-grade dysplasia. While all cases of in situ esophageal adenocarcinoma showed GATA6 expression we observed complete loss of GATA6 expression in 17% of esophageal adenocarcinoma samples. Conclusions: GATA6 is absent in squamous epithelium but its expression increases along the metaplasia-dysplasia carcinoma sequence. GATA6 expression remains predominantly present in esophageal adenocarcinoma, however, its expression is lost in a subset of samples. Analysis of the relation between GATA6 expression and clinicopathological characteristics in esophageal adenocarcinoma is pending.

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Song, Zhipeng, Lu Chen, Shuchao Pang, and Bo Yan. "Molecular genetic study on GATA5 gene promoter in acute myocardial infarction." PLOS ONE 16, no. 3 (March 8, 2021): e0248203. http://dx.doi.org/10.1371/journal.pone.0248203.

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Background Acute myocardial infarction (AMI) is a severe type of coronary artery disease, caused by coronary occlusion and followed by cardiac ischaemia. GATA binding protein 5 (GATA5) is an important member of GATA family and plays an important role in vascular inflammation, endothelial function, oxidative stress and cell metabolism. Previous studies have shown that the DNA sequence variants (DSVs) in GATA4 and GATA6 promoter can increase susceptibility to AMI. In this study, we explored the relationship between GATA5 promoter and AMI for the first time, hoping to provide a new genetic basis for understanding the pathogenesis of AMI. Methods GATA5 promoter was sequenced in 683 individuals (332 AMI patients and 351 controls). The transcriptional activity of the GATA5 promoter with or without DSVs in HEK-293 cells, H9c2 cells and primary neonatal rat cardiomyocytes were examined by Promega Dual-Luciferase® Reporter Assay system. Electrophoretic mobility shift assay (EMSA) was performed to explore whether the DSVs interfered with the binding of transcription factors (TFs). Results Nine mutations have been found in GATA5 promoter, eight of them evidently altered the transcriptional activity of the GATA5 promoter, five of them disrupted the binding of TFs (such as farnesoid X receptor). Furthermore, haplotype AT (across rs80197101 and rs77067995) is a dangerous haplotype of AMI. Genotype GA and allele A of rs80197101 and genotype CT and allele T of rs77067995 are the risk factors of AMI. Conclusions DSVs in GATA5 promoter can increase susceptibility to AMI. But the mechanism remains to be verified in vivo.

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Pihlajoki, Marjut, Elisabeth Gretzinger, Rebecca Cochran, Antti Kyrönlahti, Anja Schrade, Theresa Hiller, Laura Sullivan, et al. "Conditional Mutagenesis of Gata6 in SF1-Positive Cells Causes Gonadal-Like Differentiation in the Adrenal Cortex of Mice." Endocrinology 154, no. 5 (March 7, 2013): 1754–67. http://dx.doi.org/10.1210/en.2012-1892.

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Abstract Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.

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Sam, Jessica, Emily J. Mercer, Ingrid Torregroza, Kelly M. Banks, and Todd Evans. "Specificity, redundancy and dosage thresholds among gata4/5/6 genes during zebrafish cardiogenesis." Biology Open 9, no. 6 (June 15, 2020): bio053611. http://dx.doi.org/10.1242/bio.053611.

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ABSTRACTThe Gata4/5/6 sub-family of zinc finger transcription factors regulate many aspects of cardiogenesis. However, critical roles in extra-embryonic endoderm also challenge comprehensive analysis during early mouse cardiogenesis, while zebrafish models have previously relied on knockdown assays. We generated targeted deletions to disrupt each gata4/5/6 gene in zebrafish and analyzed cardiac phenotypes in single, double and triple mutants. The analysis confirmed that loss of gata5 causes cardia bifida and validated functional redundancies for gata5/6 in cardiac precursor specification. Surprisingly, we discovered that gata4 is dispensable for early zebrafish development, while loss of one gata4 allele can suppress the bifid phenotype of the gata5 mutant. The gata4 mutants eventually develop an age-dependent cardiomyopathy. By combining combinations of mutant alleles, we show that cardiac specification depends primarily on an overall dosage of gata4/5/6 alleles rather than a specific gene. We also identify a specific role for gata6 in controlling ventricle morphogenesis through regulation of both the first and second heart field, while loss of both gata4/6 eliminates the ventricle. Thus, different developmental programs are dependent on total dosage, certain pairs, or specific gata4/5/6 genes during embryonic cardiogenesis.This article has an associated First Person interview with the first author of the paper.

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Carrasco, Manuel, Irene Delgado, Bernat Soria, Francisco Martín, and Anabel Rojas. "GATA4 and GATA6 control mouse pancreas organogenesis." Journal of Clinical Investigation 122, no. 10 (October 1, 2012): 3504–15. http://dx.doi.org/10.1172/jci63240.

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Wang, Yishu, Enhang Lu, Riqiang Bao, Ping Xu, Fen Feng, Weihui Wen, Qiming Dong, et al. "Notch signalling regulates steroidogenesis in mouse ovarian granulosa cells." Reproduction, Fertility and Development 31, no. 6 (2019): 1091. http://dx.doi.org/10.1071/rd18281.

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The Notch signalling pathway in the mammalian ovary regulates granulosa cell proliferation. However, the effects of Notch signalling on steroidogenesis are unclear. In this study we cultured mouse ovarian granulosa cells from preantral follicles invitro and observed the effect of Notch signalling on steroidogenesis through overexpression, knockdown and inhibition of Notch signalling. Activation of Notch signalling decreased progesterone and oestrogen secretion. In contrast, inhibition of Notch signalling increased the production of progesterone and oestrogen. Expression of the genes for steroidogenic-related enzymes, including 3β-hydroxysteroid dehydrogenase, p450 cholesterol side-chain cleavage enzyme and aromatase, was repressed after stimulation of Notch signalling. The expression of upstream transcription factors, including steroidogenic factor 1 (SF1), Wilms’ tumour 1 (Wt1), GATA-binding protein 4 (Gata4) and Gata6, was also inhibited after stimulation of Notch signalling. Production of interleukin (IL)-6 was positively correlated with Notch signalling and negatively correlated with the expression of these transcription factors and enzymes. In conclusion, Notch signalling regulated progesterone and oestrogen secretion by affecting the expression of upstream transcription factors SF1, Wt1, Gata4 and Gata6, as well as downstream steroidogenic-related enzymes. IL-6, which may be regulated directly by Notch signalling, may contribute to this process. Our findings add to the understanding of the diverse functions of Notch signalling in the mammalian ovary.

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Fischer, Andreas, Jürgen Klattig, Burkhard Kneitz, Holger Diez, Manfred Maier, Bettina Holtmann, Christoph Englert, and Manfred Gessler. "Hey Basic Helix-Loop-Helix Transcription Factors Are Repressors of GATA4 and GATA6 and Restrict Expression of the GATA Target Gene ANF in Fetal Hearts." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 8960–70. http://dx.doi.org/10.1128/mcb.25.20.8960-8970.2005.

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ABSTRACT The Hey basic helix-loop-helix transcription factors are downstream effectors of Notch signaling in the cardiovascular system. Mice lacking Hey2 develop cardiac hypertrophy, often associated with congenital heart defects, whereas combined Hey1/Hey2 deficiency leads to severe vascular defects and embryonic lethality around embryonic day E9.5. The molecular basis of these disorders is poorly understood, however, since target genes of Hey transcription factors in the affected tissues remain elusive. To identify genes regulated by Hey factors we have generated a conditional Hey1 knockout mouse. This strain was used to generate paired Hey2- and Hey1/2-deficient embryonic stem cell lines. Comparison of these cell lines by microarray analysis identified GATA4 and GATA6 as differentially expressed genes. Loss of Hey1/2 leads to elevated GATA4/6 and ANF mRNA levels in embryoid bodies, while forced expression of Hey factors strongly represses expression of the GATA4 and GATA6 promoter in various cell lines. In addition, the promoter activity of the GATA4/6 target gene ANF was inhibited by Hey1, Hey2, and HeyL. Protein interaction and mutation analyses suggest that repression is due to direct binding of Hey proteins to GATA4 and GATA6, blocking their transcriptional activity. In Hey2-deficient fetal hearts we observed elevated mRNA levels of ANF and CARP. Expression of ANF and Hey2 is normally restricted to the trabecular and compact myocardial layer, respectively. Intriguingly, loss of Hey2 leads to ectopic ANF expression in the compact layer, suggesting a direct role for Hey2 in limiting ANF expression in this cardiac compartment.

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Moriguchi, Takashi. "Development and Carcinogenesis: Roles of GATA Factors in the Sympathoadrenal and Urogenital Systems." Biomedicines 9, no. 3 (March 15, 2021): 299. http://dx.doi.org/10.3390/biomedicines9030299.

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The GATA family of transcription factors consists of six proteins (GATA1-6) that control a variety of physiological and pathological processes. In particular, GATA2 and GATA3 are coexpressed in a number of tissues, including in the urogenital and sympathoadrenal systems, in which both factors participate in the developmental process and tissue maintenance. Furthermore, accumulating studies have demonstrated that GATA2 and GATA3 are involved in distinct types of inherited diseases as well as carcinogenesis in diverse tissues. This review summarizes our current knowledge of how GATA2 and GATA3 participate in the transcriptional regulatory circuitry during the development of the sympathoadrenal and urogenital systems, and how their dysregulation results in the carcinogenesis of neuroblastoma, renal urothelial, and gynecologic cancers.

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Ferreira, Sandra, David Devadason, Louise Denvir, Anna Seale, and Girish Gupte. "GATA6 Mutation." Journal of Pediatric Gastroenterology and Nutrition 64, no. 5 (May 2017): e134-e135. http://dx.doi.org/10.1097/mpg.0000000000000691.

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Walker, Emily M., Cayla A. Thompson, and Michele A. Battle. "GATA4 and GATA6 regulate intestinal epithelial cytodifferentiation during development." Developmental Biology 392, no. 2 (August 2014): 283–94. http://dx.doi.org/10.1016/j.ydbio.2014.05.017.

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Crispino, John D., and Marshall S. Horwitz. "GATA factor mutations in hematologic disease." Blood 129, no. 15 (April 13, 2017): 2103–10. http://dx.doi.org/10.1182/blood-2016-09-687889.

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Abstract GATA family proteins play essential roles in development of many cell types, including hematopoietic, cardiac, and endodermal lineages. The first three factors, GATAs 1, 2, and 3, are essential for normal hematopoiesis, and their mutations are responsible for a variety of blood disorders. Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. Conversely, germ line mutations in GATA2 are associated with GATA2 deficiency syndrome, whereas acquired mutations are seen in myelodysplastic syndrome, acute myeloid leukemia, and in blast crisis transformation of chronic myeloid leukemia. The fact that mutations in these genes are commonly seen in blood disorders underscores their critical roles and highlights the need to develop targeted therapies for transcription factors. This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.

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Padua, Maria B., Tianyu Jiang, Deborah A. Morse, Shawna C. Fox, Heather M. Hatch, and Sergei G. Tevosian. "Combined Loss of the GATA4 and GATA6 Transcription Factors in Male Mice Disrupts Testicular Development and Confers Adrenal-Like Function in the Testes." Endocrinology 156, no. 5 (February 10, 2015): 1873–86. http://dx.doi.org/10.1210/en.2014-1907.

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The roles of the GATA4 and GATA6 transcription factors in testis development were examined by simultaneously ablating Gata4 and Gata6 with Sf1Cre (Nr5a1Cre). The deletion of both genes resulted in a striking testicular phenotype. Embryonic Sf1Cre; Gata4flox/flox Gata6flox/flox (conditional double mutant) testes were smaller than control organs and contained irregular testis cords and fewer gonocytes. Gene expression analysis revealed significant down-regulation of Dmrt1 and Mvh. Surprisingly, Amh expression was strongly up-regulated and remained high beyond postnatal day 7, when it is normally extinguished. Neither DMRT1 nor GATA1 was detected in the Sertoli cells of the mutant postnatal testes. Furthermore, the expression of the steroidogenic genes Star, Cyp11a1, Hsd3b1, and Hsd17b3 was low throughout embryogenesis. Immunohistochemical analysis revealed a prominent reduction in cytochrome P450 side-chain cleavage enzyme (CYP11A1)- and 3β-hydroxysteroid dehydrogenase-positive (3βHSD) cells, with few 17α-hydroxylase/17,20 lyase-positive (CYP17A1) cells present. In contrast, in postnatal Sf1Cre; Gata4flox/flox Gata6flox/flox testes, the expression of the steroidogenic markers Star, Cyp11a1, and Hsd3b6 was increased, but a dramatic down-regulation of Hsd17b3, which is required for testosterone synthesis, was observed. The genes encoding adrenal enzymes Cyp21a1, Cyp11b1, Cyp11b2, and Mcr2 were strongly up-regulated, and clusters containing numerous CYP21A2-positive cells were localized in the interstitium. These data suggest a lack of testis functionality, with a loss of normal steroidogenic testis function, concomitant with an expansion of the adrenal-like cell population in postnatal conditional double mutant testes. Sf1Cre; Gata4flox/flox Gata6flox/flox animals of both sexes lack adrenal glands; however, despite this deficiency, males are viable in contrast to the females of the same genotype, which die shortly after birth.

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Viger, Robert S., Séverine Mazaud Guittot, Mikko Anttonen, David B. Wilson, and Markku Heikinheimo. "Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease." Molecular Endocrinology 22, no. 4 (April 1, 2008): 781–98. http://dx.doi.org/10.1210/me.2007-0513.

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The WGATAR motif is a common nucleotide sequence found in the transcriptional regulatory regions of numerous genes. In vertebrates, these motifs are bound by one of six factors (GATA1 to GATA6) that constitute the GATA family of transcriptional regulatory proteins. Although originally considered for their roles in hematopoietic cells and the heart, GATA factors are now known to be expressed in a wide variety of tissues where they act as critical regulators of cell-specific gene expression. This includes multiple endocrine organs such as the pituitary, pancreas, adrenals, and especially the gonads. Insights into the functional roles played by GATA factors in adult organ systems have been hampered by the early embryonic lethality associated with the different Gata-null mice. This is now being overcome with the generation of tissue-specific knockout models and other knockdown strategies. These approaches, together with the increasing number of human GATA-related pathologies have greatly broadened the scope of GATA-dependent genes and, importantly, have shown that GATA action is not necessarily limited to early development. This has been particularly evident in endocrine organs where GATA factors appear to contribute to the transcription of multiple hormone-encoding genes. This review provides an overview of the GATA family of transcription factors as they relate to endocrine function and disease.

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Huo, Xiaoxia, Houmin Zhou, and Tiantian Li. "MicroRNA-4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA-Binding Protein 6." BioMed Research International 2021 (April 9, 2021): 1–9. http://dx.doi.org/10.1155/2021/6616982.

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MicroRNAs (miRs) are regulators of the formation and development of hepatocellular carcinoma (HCC). The biological role of miR-4325 in HCC has yet to be determined. This study is aimed at dissecting the role of miR-4325 in HCC and the underlying mechanism. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect miR-4325 expression in HCC tissue specimens and cells. Cell proliferation, migration, and invasion were assessed by using the MTT assay and Transwell assay, respectively. The miR-4325 target was predicted based on bioinformatics analysis and validated using the dual-luciferase reporter assay. Rescue experiments in the cells were utilized to functionally characterize the downstream molecular targets of miR-4325. We observed that miR-4325 expression levels were significantly reduced in both HCC tissue specimens and cell lines. Meanwhile, a lower miR-4325 level was associated with a poorer prognosis. Gain and loss of function assays revealed that miR-4325 markedly downregulated HCC cell growth, migration, and invasion. Moreover, we identified GATA-binding protein 6 (GATA6) as a miR-4325 target and found that GATA6 was abnormally expressed in HCC. Rescue assays demonstrated that the regulatory function of miR-4325 in HCC was mediated by GATA6. Taken together, miR-4325 suppresses HCC cell growth, migration, and invasion by targeting GATA6, suggesting that miR-4325 may potentially serve as a novel therapeutic target for HCC.

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Tevosian, Sergei G., Elizabeth Jiménez, Heather M. Hatch, Tianyu Jiang, Deborah A. Morse, Shawna C. Fox, and Maria B. Padua. "Adrenal Development in Mice Requires GATA4 and GATA6 Transcription Factors." Endocrinology 156, no. 7 (May 1, 2015): 2503–17. http://dx.doi.org/10.1210/en.2014-1815.

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Song, S. H., M. S. Jeon, J. W. Nam, J. K. Kang, Y. J. Lee, J. Y. Kang, H. P. Kim, S. W. Han, G. H. Kang, and T. Y. Kim. "Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer." Oncogene 37, no. 8 (November 6, 2017): 993–1004. http://dx.doi.org/10.1038/onc.2017.397.

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Yang, Jie, Pei Lu, Mao Li, Chenchao Yan, Tianzhe Zhang, and Wei Jiang. "GATA6-AS1 Regulates GATA6 Expression to Modulate Human Endoderm Differentiation." Stem Cell Reports 15, no. 3 (September 2020): 694–705. http://dx.doi.org/10.1016/j.stemcr.2020.07.014.

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Keijzer, R., M. van Tuyl, C. Meijers, M. Post, D. Tibboel, F. Grosveld, and M. Koutsourakis. "The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development." Development 128, no. 4 (February 15, 2001): 503–11. http://dx.doi.org/10.1242/dev.128.4.503.

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Recent loss-of-function studies in mice show that the transcription factor GATA6 is important for visceral endoderm differentiation. It is also expressed in early bronchial epithelium and the observation that this tissue does not receive any contribution from Gata6 double mutant embryonic stem (ES) cells in chimeric mice suggests that GATA6 may play a crucial role in lung development. The aim of this study was to determine the role of GATA6 in fetal pulmonary development. We show that Gata6 mRNA is expressed predominantly in the developing pulmonary endoderm and epithelium, but at E15.5 also in the pulmonary mesenchyme. Blocking or depleting GATA6 function results in diminished branching morphogenesis both in vitro and in vivo. TTF1 expression is unaltered in chimeric lungs whereas SPC and CC10 expression are attenuated in abnormally branched areas of chimeric lungs. Chimeras generated in a ROSA26 background show that endodermal cells in these abnormally branched areas are derived from Gata6 mutant ES cells, implicating that the defect is intrinsic to the endoderm. Taken together, these data demonstrate that GATA6 is not essential for endoderm specification, but is required for normal branching morphogenesis and late epithelial cell differentiation.

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Gharibeh, Lara, Abir Yamak, Jamieson Whitcomb, Aizhu Lu, Mathieu Joyal, Hiba Komati, Wenbin Liang, Céline Fiset, and Mona Nemer. "GATA6 is a regulator of sinus node development and heart rhythm." Proceedings of the National Academy of Sciences 118, no. 1 (December 21, 2020): e2007322118. http://dx.doi.org/10.1073/pnas.2007322118.

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The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.

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Liu, Jielin, Henghui Cheng, Menglan Xiang, Lun Zhou, Bingruo Wu, Ivan P. Moskowitz, Ke Zhang, and Linglin Xie. "Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development." PLOS Genetics 15, no. 5 (May 23, 2019): e1007711. http://dx.doi.org/10.1371/journal.pgen.1007711.

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Xuan, Shouhong, Matthew Borok, Stephen Duncan, and Lori Sussel. "Transcription factors Gata4 and Gata6 play compensatory roles in pancreas development." Developmental Biology 356, no. 1 (August 2011): 240. http://dx.doi.org/10.1016/j.ydbio.2011.05.422.

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Kordus, Richard J., Yvonne Y. Hui, and Holly A. LaVoie. "GATA4 and GATA6 Reduction Increase DIO2 Expression in Porcine Granulosa Cells." Biology of Reproduction 81, Suppl_1 (July 1, 2009): 520. http://dx.doi.org/10.1093/biolreprod/81.s1.520.

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Liang, Qiangrong, Leon J. De Windt, Sandra A. Witt, Thomas R. Kimball, Bruce E. Markham, and Jeffery D. Molkentin. "The Transcription Factors GATA4 and GATA6 Regulate Cardiomyocyte Hypertrophyin Vitroandin Vivo." Journal of Biological Chemistry 276, no. 32 (May 16, 2001): 30245–53. http://dx.doi.org/10.1074/jbc.m102174200.

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Xuan, Shouhong, Matthew J. Borok, Kimberly J. Decker, Michele A. Battle, Stephen A. Duncan, Michael A. Hale, Raymond J. Macdonald, and Lori Sussel. "Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis." Journal of Clinical Investigation 122, no. 10 (October 1, 2012): 3516–28. http://dx.doi.org/10.1172/jci63352.

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Soini, Tea, Marjut Pihlajoki, Noora Andersson, Jouko Lohi, Kari A. Huppert, David A. Rudnick, Stacey S. Huppert, David B. Wilson, Mikko P. Pakarinen, and Markku Heikinheimo. "Transcription factor GATA6: a novel marker and putative inducer of ductal metaplasia in biliary atresia." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 5 (May 1, 2018): G547—G558. http://dx.doi.org/10.1152/ajpgi.00362.2017.

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Biliary atresia (BA), a neonatal liver disease, is characterized by obstruction of extrahepatic bile ducts with subsequent cholestasis, inflammation, and progressive liver fibrosis. To gain insights into the pathophysiology of BA, we focused attention on GATA6, a transcription factor implicated in biliary development. Early in fetal development GATA6 expression is evident in cholangiocytes and hepatocytes, but by late gestation it is extinguished in hepatocytes. Utilizing a unique set of BA liver samples collected before and after successful portoenterostomy (PE), we found that GATA6 expression is markedly upregulated in hepatocytes of patients with BA compared with healthy and cholestatic disease controls. This upregulation is recapitulated in two murine models simulating bile duct obstruction and intrahepatic bile ductule expansion. GATA6 expression in BA livers correlates with two established negative prognostic indicators (age at PE, degree of intrahepatic bile ductule expansion) and decreases after normalization of serum bilirubin by PE. GATA6 expression in BA livers correlates with expression of known regulators of cholangiocyte differentiation ( JAGGED1, HNF1β, and HNF6). These same genes are upregulated after enforced expression of GATA6 in human hepatocyte cell models. In conclusion, GATA6 is a novel marker and a putative driver of hepatocyte-cholangiocyte metaplasia in BA, and its expression in hepatocytes is downregulated after successful PE. NEW & NOTEWORTHY A pathological hallmark in the liver of patients with biliary atresia is ductular reaction, an expansion of new bile ductules that are thought to arise from conversion of mature hepatocytes. Here, we show that transcription factor GATA6 is a marker and potential driver of hepatocyte ductal metaplasia in biliary atresia. Hepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.

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Ghamari, Alireza, Gabriela Pregerning, Ernest Fraenkel, and Alan B. Cantor. "GATA Factor Switching during Erythroid Differentiation Is Facilitated By FBW7 Mediated Clearance of GATA2." Blood 128, no. 22 (December 2, 2016): 1479. http://dx.doi.org/10.1182/blood.v128.22.1479.1479.

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Abstract Erythroid differentiation is controlled by the dynamic exchange of GATA family transcription factors. During early erythroid maturation, high GATA2 levels activate progenitor genes such as c-kit-, c-myc, and GATA2 itself. In contrast, GATA1 levels are low in early progenitor cells, but rise during terminal maturation. During this process GATA1 turns off GATA2 controlled early progenitor genes and activates terminal maturation genes, such as globin genes, heme biosynthesis enzymes, and iron transporters. This involves the exchange of GATA1 for GATA2 at key chromatin sites, the so-called "GATA factor switch". GATA factor switching is facilitated by the much shorter half-life of GATA2 (~30-60 min) compared to GATA1 (>4-6 hrs). We and others recently demonstrated that the E3 ubiquitin ligase adaptor protein FBW7 contributes to GATA2's relative instability. This prompted us to dissect the role of FBW7 during GATA switching and erythroid differentiation. We deleted the Fbw7 gene using CRISPR/Cas9 gene editing in the inducible G1-ER murine erythroid cell line. This resulted in the delayed clearance of GATA2 during differentiation. RNA-seq analysis at an early time points (7 hr) demonstrated impaired repression of GATA2 regulated genes and reduced activation of GATA1 target genes. Globally, altered gene expression was enriched for GATA factor switch genes. This ultimately resulted in delayed erythroid maturation. We also found that Fbw7 mRNA transcript levels increase during erythroid maturation in wild type cells. We identified a site ~40kb upstream of the Fbw7 gene transcriptional start site, which is itself a GATA factor switch site. We propose that FBW7 facilitates GATA factor switching by promoting the clearance of GATA2 from GATA factor switch sites. Moreover, we suggest that GATA factor switching at the Fbw7 locus itself reinforces the commitment of erythroid cells to terminal maturation, by enhancing the clearance of GATA2 and other Fbw7 progenitor target gene proteins such as c-Myc and c-Myb. As Fbw7 recognition of GATA2 requires phosphorylation of GATA2's degron motif, this suggests that signaling pathways, acting through Fbw7, may modulate erythroid maturation kinetics. Disclosures No relevant conflicts of interest to declare.

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Gautier, Emmanuel L., Stoyan Ivanov, Jesse W. Williams, Stanley Ching-Cheng Huang, Genevieve Marcelin, Keke Fairfax, Peter L. Wang, et al. "Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival." Journal of Experimental Medicine 211, no. 8 (July 14, 2014): 1525–31. http://dx.doi.org/10.1084/jem.20140570.

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The transcription factor Gata6 regulates proliferation and differentiation of epithelial and endocrine cells and cancers. Among hematopoietic cells, Gata6 is expressed selectively in resident peritoneal macrophages. We thus examined whether the loss of Gata6 in the macrophage compartment affected peritoneal macrophages, using Lyz2-Cre x Gata6flox/flox mice to tackle this issue. In Lyz2-Cre x Gata6flox/flox mice, the resident peritoneal macrophage compartment, but not macrophages in other organs, was contracted, with only a third the normal number of macrophages remaining. Heightened rates of death explained the marked decrease in peritoneal macrophage observed. The metabolism of the remaining macrophages was skewed to favor oxidative phosphorylation and alternative activation markers were spontaneously and selectively induced in Gata6-deficient macrophages. Gene expression profiling revealed perturbed metabolic regulators, including aspartoacylase (Aspa), which facilitates generation of acetyl CoA. Mutant mice lacking functional Aspa phenocopied the higher propensity to death and led to a contraction of resident peritoneal macrophages. Thus, Gata6 regulates differentiation, metabolism, and survival of resident peritoneal macrophages.

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Duncan, S. A. "Generation of embryos directly from embryonic stem cells by tetraploid embryo complementation reveals a role for GATA factors in organogenesis." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1534–36. http://dx.doi.org/10.1042/bst0331534.

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Gene targeting in ES (embryonic stem) cells has been used extensively to study the role of proteins during embryonic development. In the traditional procedure, this requires the generation of chimaeric mice by introducing ES cells into blastocysts and allowing them to develop to term. Once chimaeric mice are produced, they are bred into a recipient mouse strain to establish germline transmission of the allele of interest. Although this approach has been used very successfully, the breeding cycles involved are time consuming. In addition, genes that are essential for organogenesis often have roles in the formation of extra-embryonic tissues that are essential for early stages of post-implantation development. For example, mice lacking the GATA transcription factors, GATA4 or GATA6, arrest during gastrulation due to an essential role for these factors in differentiation of extra-embryonic endoderm. This lethality has frustrated the study of these factors during the development of organs such as the liver and heart. Extraembryonic defects can, however, be circumvented by generating clonal mouse embryos directly from ES cells by tetraploid complementation. Here, we describe the usefulness and efficacy of this approach using GATA factors as an example.

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Holtzinger, Audrey, and Todd Evans. "Gata5 and Gata6 are functionally redundant in zebrafish for specification of cardiomyocytes." Developmental Biology 312, no. 2 (December 2007): 613–22. http://dx.doi.org/10.1016/j.ydbio.2007.09.018.

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Xuan, Shouhong, and Lori Sussel. "GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling." Development 143, no. 5 (March 1, 2016): 780–86. http://dx.doi.org/10.1242/dev.127217.

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Xin, M., C. A. Davis, J. D. Molkentin, C. L. Lien, S. A. Duncan, J. A. Richardson, and E. N. Olson. "A threshold of GATA4 and GATA6 expression is required for cardiovascular development." Proceedings of the National Academy of Sciences 103, no. 30 (July 17, 2006): 11189–94. http://dx.doi.org/10.1073/pnas.0604604103.

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Kuo, Jong-Tar, Hsiao-En Tsai, Ching-Ting Lin, Chih-I. Lee, Pei-Ling Lee, Yu-Rong Ruan, Jeng-Jiann Chiu, and Ding-Yu Lee. "Low Levels of MicroRNA-10a in Cardiovascular Endothelium and Blood Serum Are Related to Human Atherosclerotic Disease." Cardiology Research and Practice 2021 (July 15, 2021): 1–7. http://dx.doi.org/10.1155/2021/1452917.

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Background. MicroRNA-10a (miR-10a) inhibits transcriptional factor GATA6 to repress inflammatory GATA6/VCAM-1 signaling, which is regulated by blood flow to affect endothelial function/dysfunction. This study aimed to identify the expression patterns of miR-10a/GATA6/VCAM-1 in vivo and study their implications in the pathophysiology of human coronary artery disease (CAD), i.e., atherosclerosis. Methods. Human atherosclerotic coronary arteries and nondiseased arteries were used to detect the expressions of miR-10a/GATA6/VCAM-1 in pathogenic vs. normal conditions. In addition, sera from CAD patients and healthy subjects were collected to detect the level of circulating miR-10a. Results. The comparison of human atherosclerotic coronary arteries with nondiseased arteries demonstrated that lower levels of endothelial miR-10a are related to human atherogenesis. Moreover, GATA6/VCAM-1 (a downstream target of miR-10a) was highly expressed in the endothelium, accompanied by the reduced levels of miR-10a during the development of human atherosclerosis. In addition, CAD patients had a significantly lower concentration of miR-10a in their serum compared to healthy subjects. Conclusions. Our findings suggest that low miR-10a and high GATA6/VCAM-1 in the cardiovascular endothelium correlates to the development of human atherosclerotic lesions, suggesting that miR-10a signaling has the potential to be developed as a biomarker for human atherosclerosis.

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Ferreira, Rita, Albert Wai, Ritsuko Shimizu, Nynke Gillemans, Robbert Rottier, Marieke von Lindern, Kinuko Ohneda, Frank Grosveld, Masayuki Yamamoto, and Sjaak Philipsen. "Dynamic regulation of Gata factor levels is more important than their identity." Blood 109, no. 12 (June 15, 2007): 5481–90. http://dx.doi.org/10.1182/blood-2006-11-060491.

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Abstract Three Gata transcription factors (Gata1, -2, and -3) are essential for hematopoiesis. These factors are thought to play distinct roles because they do not functionally replace each other. For instance, Gata2 messenger RNA (mRNA) expression is highly elevated in Gata1-null erythroid cells, yet this does not rescue the defect. Here, we test whether Gata2 and -3 transgenes rescue the erythroid defect of Gata1-null mice, if expressed in the appropriate spatiotemporal pattern. Gata1, -2, and -3 transgenes driven by β-globin regulatory elements, directing expression to late stages of differentiation, fail to rescue erythropoiesis in Gata1-null mutants. In contrast, when controlled by Gata1 regulatory elements, directing expression to the early stages of differentiation, Gata1, -2, and -3 do rescue the Gata1-null phenotype. The dramatic increase of endogenous Gata2 mRNA in Gata1-null progenitors is not reflected in Gata2 protein levels, invoking translational regulation. Our data show that the dynamic spatiotemporal regulation of Gata factor levels is more important than their identity and provide a paradigm for developmental control mechanisms that are hard-wired in cis-regulatory elements.

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Zhou, Li, Hua Ning, Haibin Wei, Tiantian Xu, Xindi Zhao, Ai Fu, Qianyu Qian, Zhen Yang, Xiaobing Dou, and Songtao Li. "A Novel STAT3-Mediated GATA6 Pathway Contributes to tert-Butylhydroquinone- (tBHQ-) Protected TNFα-Activated Vascular Cell Adhesion Molecule 1 (VCAM-1) in Vascular Endothelium." Oxidative Medicine and Cellular Longevity 2020 (November 14, 2020): 1–17. http://dx.doi.org/10.1155/2020/6584059.

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The activation of vascular cell adhesion molecule 1 (VCAM-1) in vascular endothelial cells has been well considered implicating in the initiation and processing of atherosclerosis. Oxidative stress is mechanistically involved in proatherosclerotic cytokine-induced VCAM-1 activation. tert-Butylhydroquinone (tBHQ), a synthetic phenolic antioxidant used for preventing lipid peroxidation of food, possesses strongly antioxidant capacity against oxidative stress-induced dysfunction in various pathological process. Here, we investigated the protective role of tBHQ on tumor necrosis factor alpha- (TNFα-) induced VCAM-1 activation in both aortic endothelium of mice and cultured human vascular endothelial cells and uncovered its potential mechanisms. Our data showed that tBHQ treatment significantly reversed TNFα-induced activation of VCAM-1 at both transcriptional and protein levels. The mechanistic study revealed that inhibiting neither nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nor autophagy blocked the beneficial role of tBHQ. Alternatively, tBHQ intervention markedly alleviated TNFα-increased GATA-binding protein 6 (GATA6) mRNA and protein expressions and its translocation into nucleus. Further investigation indicated that tBHQ-inhibited signal transducer and activator of transcription 3 (STAT3) but not mitogen-activated protein kinase (MAPK) pathway contributed to its protective role against VCAM-1 activation via regulating GATA6. Collectively, our data demonstrated that tBHQ prevented TNFα-activated VCAM-1 via a novel STAT3/GATA6-involved pathway. tBHQ could be a potential candidate for the prevention of proatherosclerotic cytokine-caused inflammatory response and further dysfunctions in vascular endothelium.

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Ghamari, Alireza, Elizabeth Jaensch, Richard Giadone, Thomas E. Akie, Jian Xu, Daniel Bauer, Stuart H. Orkin, and Alan B. Cantor. "An SCF-FBXW7 Ubiquitin Ligase Mediated Feedback Loop Facilitates GATA Factor Switching and Reinforces Commitment to Terminal Erythroid Maturation." Blood 124, no. 21 (December 6, 2014): 245. http://dx.doi.org/10.1182/blood.v124.21.245.245.

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Abstract The GATA family transcription factors GATA2 and GATA1 play reciprocal roles during terminal erythroid and megakaryocytic maturation. GATA2 is expressed early in hematopoiesis and is required for early progenitor cell proliferation and survival. It must be down regulated in order for terminal maturation to occur. In contrast, GATA1 increases in expression during erythropoiesis and megakaryopoiesis, and is required for terminal maturation of these lineages. During this process, GATA1 displaces GATA2 at a large number of chromatin loci, typically leading to repression of early progenitor genes and activation of terminal maturation genes. This “GATA factor switch” is facilitated by the considerably shorter half-life of GATA2 (~30 min) compared to GATA1 (>4-6 hours). GATA2’s short half-life is mediated by ubiquitin-proteosomal degradation mechanisms. Yet the ubiquitin complex(es) responsible for GATA2-specific clearance has not been identified. In this study, we show that the Skip1-Cullin-Fbox (SCF) substrate recognition factor Fbxw7 is involved in GATA2 ubiquitin-mediated degradation. Proteomic and co-immunoprecipitation experiments show physical association of Fbxw7 with GATA2, but not GATA1. CRISPR/Cas9 deletion of Fbxw7 in G1ER4 cells results in elevated GATA2 steady-state protein levels, a prolonged GATA2 half-life, delayed GATA2 clearance upon estradiol induction, and impaired erythroid terminal maturation. Importantly, Fbxw7 mRNA and protein levels normally increase during terminal erythroid maturation and this occurs in a GATA1 dependent manner. We identified a key cis-regulatory element upstream of the Fbxw7 gene that is occupied by GATA2 during early erythropoiesis, but becomes bound by GATA1/TAL1 during late erythroid maturation in induced G1-ER4 cells and human CD34+ in vitro differentiated erythroblasts. This is accompanied by the acquisition of active enhancer histone marks at this site. Deletion of this regulatory element in G1ER4 cells blocks the GATA1 dependent increase in Fbxw7 mRNA transcript levels during erythroid cell maturation. Lastly, we identified a family with congenital hypoplastic anemia (lacking mutations in all known Diamond Blackfan Anemia genes) who harbor a germline Fbxw7missense mutation. Collectively, these findings identify GATA2 as a novel Fbxw7 substrate and uncover an ubiquitin-mediated post-transcriptional GATA factor feedback loop that reinforces GATA factor switching and commitment to terminal erythroid maturation. Disclosures Cantor: Amgen: Membership on an entity's Board of Directors or advisory committees.

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Leszczyński, Paweł, Magdalena Śmiech, Aamir Salam Teeli, Effi Haque, Robert Viger, Hidesato Ogawa, Mariusz Pierzchała, and Hiroaki Taniguchi. "Deletion of the Prdm3 Gene Causes a Neuronal Differentiation Deficiency in P19 Cells." International Journal of Molecular Sciences 21, no. 19 (September 29, 2020): 7192. http://dx.doi.org/10.3390/ijms21197192.

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PRDM (PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1) homologous domain-containing) transcription factors are a group of proteins that have a significant impact on organ development. In our study, we assessed the role of Prdm3 in neurogenesis and the mechanisms regulating its expression. We found that Prdm3 mRNA expression was induced during neurogenesis and that Prdm3 gene knockout caused premature neuronal differentiation of the P19 cells and enhanced the growth of non-neuronal cells. Interestingly, we found that Gata6 expression was also significantly upregulated during neurogenesis. We further studied the regulatory mechanism of Prdm3 expression. To determine the role of GATA6 in the regulation of Prdm3 mRNA expression, we used a luciferase-based reporter assay and found that Gata6 overexpression significantly increased the activity of the Prdm3 promoter. Finally, the combination of retinoic acid receptors α and β, along with Gata6 overexpression, further increased the activity of the luciferase reporter. Taken together, our results suggest that in the P19 cells, PRDM3 contributed to neurogenesis and its expression was stimulated by the synergism between GATA6 and the retinoic acid signaling pathway.

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Leavy, Olive. "Peritoneal population depends on GATA6." Nature Reviews Immunology 14, no. 6 (May 23, 2014): 360. http://dx.doi.org/10.1038/nri3695.

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Galloway, Jenna L., Rebecca A. Wingert, Christine Thisse, Bernard Thisse, and Leonard I. Zon. "Gata-Independent Regulation of Red Cell Specific Gene Expression." Blood 106, no. 11 (November 16, 2005): 1736. http://dx.doi.org/10.1182/blood.v106.11.1736.1736.

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Abstract During vertebrate embryonic hematopoiesis, the first blood cells can be identified by expression of the transcription factor genes scl and GATA2, followed by expression of GATA1, a gene required for the erythroid lineage. A high-throughput in situ hybridization screen in zebrafish analyzed the expression pattern of 3700 clones from a hematopoietic cDNA library and discovered 24 genes with expression in the blood. Examination of gene expression in Biklf, GATA1, GATA2, and GATA1/GATA2-deficient animals revealed that most blood genes are dependent upon GATA factors for expression rather than the Krüppel-like transcription factor Biklf. Three novel genes, expressed specifically in erythroid precursors, did not require GATA factors for their expression, demonstrating that some blood genes are regulated in a GATA-independent manner. These three genes were kelch-repeat protein (kelch repeats have been implicated in diverse cellular functions from actin binding to sequestering transcriptions factors), kiaa0650, which contains an SMC-hinge domain, and testhymin, which has no known structural motifs. By using combinations of antisense morpholinos to the known hematopoietic genes biklf , GATA1, GATA2, and scl, we were able to examine the regulation of these novel genes in double and triple knock-down embryos. While expression of kelch-repeat protein was lost in the absence of GATA1 and Biklf, expression of testhymin and kiaa0650 was maintained in GATA1/GATA2/Biklf-deficient embryos, suggesting that these similarly expressed genes are differentially regulated. As with GATA1, kiaa0650 and kelch-repeat protein required Scl for their expression in the early hematopoietic mesoderm while testhymin did not. Furthermore, loss of Scl and GATA2 did not completely ablate testhymin expression, suggesting that this gene is induced by factors upstream or parallel to Scl and GATA2. Taken together, our zebrafish studies establish a regulation of gene expression by a developmental hierarchy of specific transcription factors that act in combination during blood cell maturation.

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Maitra, Meenakshi, Marie K. Schluterman, Haley A. Nichols, James A. Richardson, Cecilia W. Lo, Deepak Srivastava, and Vidu Garg. "Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development." Developmental Biology 326, no. 2 (February 2009): 368–77. http://dx.doi.org/10.1016/j.ydbio.2008.11.004.

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Journal articles on the topic 'Gata6'

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