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1
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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Bouchard, Marie France, Hiroaki Taniguchi, and Robert S. Viger. "Protein Kinase A-Dependent Synergism between GATA Factors and the Nuclear Receptor, Liver Receptor Homolog-1, Regulates Human Aromatase (CYP19) PII Promoter Activity in Breast Cancer Cells." Endocrinology 146, no. 11 (November 1, 2005): 4905–16. http://dx.doi.org/10.1210/en.2005-0187.
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Cancers, including that of the breast, are the result of multiple contributing factors including aberrant gene expression. Indeed, the CYP19 gene encoding P450 aromatase, the key enzyme for estrogen biosynthesis, is up-regulated in breast tumors predominantly via the cAMP-responsive gonad-type PII promoter, ultimately leading to increased intratumoral estrogen production and tumor growth. Thus, identifying the molecular factors involved in aromatase PII promoter regulation is essential for our understanding and treatment of the disease. Because we have previously shown activity of the murine aromatase PII promoter to be markedly up-regulated by GATA factors with respect to the gonads, we hypothesized that GATA factors are also key determinants of human PII promoter-driven aromatase transcription in breast tumors. We now show that GATA3 and GATA4 are indeed expressed in several breast cancer cells lines. Consistent with the cAMP dependence of the PII promoter, activation elicited by GATA3 or GATA4 alone and the striking synergism between GATA3 or GATA4 and the nuclear receptor liver receptor homolog (LRH)-1 was intimately linked to forskolin treatment or overexpression of protein kinase A (PKA) catalytic subunit. PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. Finally, we show that the human LRH-1 promoter is itself a target for GATA factors. Thus, taken together, our results suggest that GATA factors likely contribute to aberrant aromatase expression in breast tumors through two distinct, yet complementary mechanisms.
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Fang, Difeng, Kairong Cui, Gangqing Hu, Rama Krishna Gurram, Chao Zhong, Andrew J. Oler, Ryoji Yagi, et al. "Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation." Journal of Experimental Medicine 215, no. 5 (March 7, 2018): 1449–62. http://dx.doi.org/10.1084/jem.20171127.
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GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein–protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.
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Onodera, Koichi, Tohru Fujiwara, Yasushi Onishi, Ari Itoh-Nakadai, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, and Hideo Harigae. "GATA-2 Regulates Dendritic Cell Differentiation." Blood 126, no. 23 (December 3, 2015): 2382. http://dx.doi.org/10.1182/blood.v126.23.2382.2382.
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Abstract (Background) Dendritic cells (DCs) are critical regulators of the immune response, but their differentiation mechanism remains unclear. Heterozygous germline GATA-2 mutations in humans cause MonoMAC syndrome, characterized by monocytopenia and predisposition to myelodysplasia/acute myeloid leukemia. In this syndrome, DC count decreases profoundly, with an increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. In the present study, we analyzed the role of GATA-2 in DC differentiation and the underlying molecular mechanisms. (Method) Gata2 haploinsufficient mice (Gata2+/−: Tsai et al. Nature 1994) and tamoxifen-inducible Gata2-knockout mice (Gata2flox/flox/ER-Cre: Charles et al. Molecular Endocrinology 2006) were used. To generate conditional Gata2 knockouts in vivo, Gata2flox/flox/ER-Cre mice were intraperitoneally injected with 1-μg tamoxifen on days 1-3 and 8-10 and evaluated on days 20-22. Isolation of splenic DCs and bone marrow (BM) precursors, including LSK (Lin- Sca1+ Kit+ cell), CMP (common myeloid-restricted progenitor), GMP (granulocyte-macrophage progenitor), CLP (common lymphoid-restricted progenitor), and CDP (common dendritic cell precursor), were separated with both MACS (Miltenyi Biotech) and BD FACSAria II (BD Biosciences). For the in vitro analysis of Gata2-knockout, BM cells were cultured with CD45.1+ BM feeder cells from SJL mice (The Jackson Laboratory) with FLT3L (200 ng/mL) and 4-hydroxytamoxifen (Sigma). For transcription profiling, SurePrint G3 mouse GE microarray (Agilent) was used, and the data was subsequently analyzed with ImmGen database (http://www.immgen.org). Promoter assay was conducted with Dual Luciferase Reporter Assay system (Promega). Quantitative chromatin immunoprecipitation (ChIP) analysis was performed using CMP fraction and erythroid-myeloid-lymphoid (EML) hematopoietic precursor cell line (ATCC) with antibodies to GATA-2 (sc-9008, Santa Cruz Biotechnology). (Results) Quantitative RT-PCR analysis showed abundant Gata2 expression in LSK and CMP fractions, with detectable expression in GMP, CLP, and CDP fractions and in vitro differentiated DCs. Although the DC count did not change in Gata2 haploinsufficient mice, it significantly and profoundly decreased in Gata2 conditional knockout mice. To examine the role of GATA-2 during DC differentiation, we knocked out Gata2 during in vitro DC differentiation, starting from LSK, CMP, GMP, CLP, and CDP fractions obtained from Gata2flox/flox/ER-Cre mice. Gata2 knockout significantly decreased CD11c+ DC counts from LSK, CMP, and CDP fractions, while those from CLP and GMP were unaffected, implying the importance of GATA-2 during DC differentiation in the pathway from LSK to CDP via CMP, not via CLP nor GMP. To elucidate the underlying molecular mechanisms, we performed expression profiling with control and Gata2 -knockout DC progenitors from CMP of Gata2flox/flox/ER-Cre mice. Gata2 knockout caused >5-fold upregulation and downregulation of 67 and 63 genes, respectively. Although genes critical for the DC differentiation, e.g., Spi1, Ikzf1, and Gfi1, were not detected among the GATA-2-regulated gene ensemble, we found significant enrichment of myeloid-related and T lymphocyte-related genes among the downregulated and upregulated gene ensembles, respectively. We focused on Gata3 upregulation (7.33-fold) as a potential key mechanism contributing to Gata2 knockout-related impaired DC differentiation. Quantitative ChIP analysis with both CMP fraction and EML cell line demonstrated obvious GATA-2 chromatin occupancy at the consensus GATA-binding motif within Gata3+190 kb, which was conserved with human. Furthermore, addition of Gata3 +190 kb region to the Gata3 promoter (~0.5 kb) significantly decreased luciferase activity, which was significantly recovered by the deletion of GATA sequence within Gata3 +190 kb, in EML cells. (Conclusion) GATA-2 seems to play an important role for cell fate specification toward myeloid versus T lymphocytes, and thus contributing to the DC differentiation. Our data offer a better understanding of the pathophysiology of MonoMAC syndrome. Disclosures Fujiwara: Chugai Pharmaceuticals. Co., Ltd.: Research Funding. Fukuhara:Gilead Sciences: Research Funding. Ishizawa:GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau.
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Bottardi, Stefania, Lionel Mavoungou, Vincent Bourgoin, Nazar Mashtalir, El Bachir Affar, and Eric Milot. "Direct Protein Interactions Are Responsible for Ikaros-GATA and Ikaros-Cdk9 Cooperativeness in Hematopoietic Cells." Molecular and Cellular Biology 33, no. 16 (June 3, 2013): 3064–76. http://dx.doi.org/10.1128/mcb.00296-13.
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Ikaros (Ik) is a critical regulator of hematopoietic gene expression. Here, we established that the Ik interactions with GATA transcription factors and cyclin-dependent kinase 9 (Cdk9), a component of the positive transcription elongation factor b (P-TEFb), are required for transcriptional activation of Ik target genes. A detailed dissection of Ik-GATA and Ik-Cdk9 protein interactions indicated that the C-terminal zinc finger domain of Ik interacts directly with the C-terminal zinc fingers of GATA1, GATA2, and GATA3, whereas the N-terminal zinc finger domain of Ik is required for interaction with the kinase and T-loop domains of Cdk9. The relevance of these interactions was demonstratedin vivoin COS-7 and primary hematopoietic cells, in which Ik facilitated Cdk9 and GATA protein recruitment to gene promoters and transcriptional activation. Moreover, the oncogenic isoform Ik6 did not efficiently interact with Cdk9 or GATA proteinsin vivoand perturbed Cdk9/P-TEFb recruitment to Ik target genes, thereby affecting transcription elongation. Finally, characterization of a novel nuclear Ik isoform revealed that Ik exon 6 is dispensable for interactions with Mi2 and GATA proteins but is essential for the Cdk9 interaction. Thus, Ik is central to the Ik-GATA-Cdk9 regulatory network, which is broadly utilized for gene regulation in hematopoietic cells.
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Hosoya, Tomonori, Takashi Kuroha, Takashi Moriguchi, Dustin Cummings, Ivan Maillard, Kim-Chew Lim, and James Douglas Engel. "GATA-3 is required for early T lineage progenitor development." Journal of Experimental Medicine 206, no. 13 (November 23, 2009): 2987–3000. http://dx.doi.org/10.1084/jem.20090934.
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Most T lymphocytes appear to arise from very rare early T lineage progenitors (ETPs) in the thymus, but the transcriptional programs that specify ETP generation are not completely known. The transcription factor GATA-3 is required for the development of T lymphocytes at multiple late differentiation steps as well as for the development of thymic natural killer cells. However, a role for GATA-3 before the double-negative (DN) 3 stage of T cell development has to date been obscured both by the developmental heterogeneity of DN1 thymocytes and the paucity of ETPs. We provide multiple lines of in vivo evidence through the analysis of T cell development in Gata3 hypomorphic mutant embryos, in irradiated mice reconstituted with Gata3 mutant hematopoietic cells, and in mice conditionally ablated for the Gata3 gene to show that GATA-3 is required for ETP generation. We further show that Gata3 loss does not affect hematopoietic stem cells or multipotent hematopoietic progenitors. Finally, we demonstrate that Gata3 mutant lymphoid progenitors exhibit neither increased apoptosis nor diminished cell-cycle progression. Thus, GATA-3 is required for the cell-autonomous development of the earliest characterized thymic T cell progenitors.
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Scazzone, Concetta, Luisa Agnello, Bruna Lo Sasso, Giuseppe Salemi, Caterina Maria Gambino, Paolo Ragonese, Giuseppina Candore, et al. "FOXP3 and GATA3 Polymorphisms, Vitamin D3 and Multiple Sclerosis." Brain Sciences 11, no. 4 (March 25, 2021): 415. http://dx.doi.org/10.3390/brainsci11040415.
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Background: Regulatory T cells (Tregs) alterations have been implicated in the pathogenesis of Multiple Sclerosis (MS). Recently, a crucial role of the X-Linked Forkhead Box P3 (FoxP3) for the development and the stability of Tregs has emerged, and FOXP3 gene polymorphisms have been associated with the susceptibility to autoimmune diseases. The expression of Foxp3 in Tregs is regulated by the transcription factor GATA binding-protein 3 (GATA3) and vitamin D3. The aim of this retrospective case-control study was to investigate the potential association between FOXP3 and GATA3 genetic variants, Vitamin D3, and MS risk. Methods: We analyzed two polymorphisms in the FOXP3 gene (rs3761547 and rs3761548) and a polymorphism in the GATA3 gene (rs3824662) in 106 MS patients and 113 healthy controls. Serum 25(OH)D3 was also measured in all participants. Results: No statistically significant genotypic and allelic differences were found in the distribution of FOXP3 rs3761547 and rs3761548, or GATA3 rs3824662 in the MS patients, compared with controls. Patients that were homozygous for rs3761547 had lower 25(OH)D3 levels. Conclusions: Our findings did not show any association among FOXP3 and GATA3 SNPs, vitamin D3, and MS susceptibility.
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Zhang, Chenghua, Gangzheng Wang, Wangqiu Deng, and Taihui Li. "Distribution, evolution and expression of GATA-TFs provide new insights into their functions in light response and fruiting body development of Tolypocladium guangdongense." PeerJ 8 (August 28, 2020): e9784. http://dx.doi.org/10.7717/peerj.9784.
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Background Fungal GATA-type transcription factors (GATA-TFs) are a class of transcriptional regulators involved in various biological processes. However, their functions are rarely analyzed systematically, especially in edible or medicinal fungi, such as Tolypocladium guangdongense, which has various medicinal and food safety properties with a broad range of potential applications in healthcare products and the pharmaceutical industry. Methods GATA-TFs in T. guangdongense (TgGATAs) were identified using InterProScan. The type, distribution, and gene structure of TgGATAs were analyzed by genome-wide analyses. A phylogenetic tree was constructed to analyze their evolutionary relationships using the neighbor-joining (NJ) method. To explore the functions of GATA-TFs, conserved domains were analyzed using MEME, and cis-elements were predicted using the PlantCARE database. In addition, the expression patterns of TgGATAs under different light conditions and developmental stages were studied using qPCR. Results Seven TgGATAs were identified. They were randomly distributed on four chromosomes and contained one to four exons. Phylogenetic analysis indicated that GATA-TFs in each subgroup are highly conserved, especially for GATA1 to GATA5. Intron distribution analyses suggested that GATA1 and GATA3 possessed the most conserved gene structures. Light treatments induced the expression levels of TgGATA1 and TgGATA5-7, but the expression levels varied depending on the duration of illumination. The predicted protein structures indicate that TgGATA1 and TgGATA2 possess typical light-responsive domains and may function as photoreceptors to regulate downstream biological processes. TgGATA3 and TgGATA5 may be involved in nitrogen metabolism and siderophore biosynthesis, respectively. TgGATA6 and TgGATA7 possess unique Zn finger loop sequences, suggesting that they may have special functions. Furthermore, gene expression analysis indicated that TgGATA1 (WC1) was notably involved in mycelial color transformation, while other genes were involved in fruiting body development to some extent. These results provide valuable information to further explore the mechanisms through which TgGATAs are regulated during fruiting body development.
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Soklic, Tanja Kosak, Matija Rijavec, Mira Silar, Ana Koren, Izidor Kern, Irena Hocevar-Boltezar, and Peter Korosec. "Transcription factors gene expression in chronic rhinosinusitis with and without nasal polyps." Radiology and Oncology 53, no. 3 (July 17, 2019): 323–30. http://dx.doi.org/10.2478/raon-2019-0029.
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Abstract Background Chronic rhinosinusitis (CRS) current therapeutic approaches still fail in some patients with severe persistent symptoms and recurrences after surgery. We aimed to evaluate the master transcription factors gene expression levels of T cell subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) that could represent new, up-stream targets for topical DNAzyme treatment. Patients and methods Twenty-two newly diagnosed CRS patients (14 CRSwNP and 8 CRSsNP) were prospectively biopsied and examined histopathologically. Gene expression levels of T-box transcription factor (T-bet, TBX21), GATA binding protein 3 (GATA3), Retinoic acid-related orphan receptor C (RORC) and Forkhead box P3 (FOXP3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results Eosinophilic CRSwNP was characterized by higher level of GATA3 gene expression compared to noneosinophilic CRSwNP, whereas there was no difference in T-bet, RORC and FOXP3 between eosinophilic and noneosinophilic CRSwNP. In CRSsNP, we found simultaneous upregulation of T-bet, GATA3 and RORC gene expression levels in comparison to CRSwNP; meanwhile, there was no difference in FOXP3 gene expression between CRSwNP and CRSsNP. Conclusions In eosinophilic CRSwNP, we confirmed the type 2 inflammation by elevated GATA3 gene expression level. In CRSsNP, we unexpectedly found simultaneous upregulation of T-bet and GATA3 that is currently unexplained; however, it might originate from activated CD8+ cells, abundant in nasal mucosa of CRSsNP patients. The elevated RORC in CRSsNP could be part of homeostatic nasal immune response that might be better preserved in CRSsNP patients compared to CRSwNP patients. Further data on transcription factors expression rates in CRS phenotypes are needed.
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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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Hemeed Abbas, Zeinab, Karrar S. Zayed, Rihab H. Almudhafer, and Hanaa Hemeed Abbas. "Immunohistochemical Expression of Gata3 Gene in Patients with Breast Cancer." Pakistan Journal of Medical and Health Sciences 15, no. 8 (August 30, 2021): 2355–58. http://dx.doi.org/10.53350/pjmhs211582355.
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Breast cancer (BC) is one of the most common cancers in the world. In numerous tissues, including the breast, GATA3 plays an important role in stimulating proliferation and differentiation. The main aims of this study is determining the types of BC (IDC and ILC) then the estimation of the role of GATA3 protein expression by immunohistochemical staining method (IHC) in BC patients and control groups as a biomarker. The present study was done during the period from October 2020 to April 2021. Sixty seven tissue samples block embedded in wax taken from BC female patients and thirty four of normal non-tumoral breast tissue as a control group collected randomly with their data from three private pathological clinics, these blocks have been prepared between (2014 – 2021), three pathologists re-evaluate each pathologic material. Regarding to IHC GATA3 protein expression, after histological re-evaluation of slides, the rate of IDC was 80.6% (54 patients) and of ILC was (19.4%) (13 patients).The scoring system +1 (37.3%) and +2(19.4%) increased significantly in BC patients than control (P=0.001), in addition to, the nuclear positive expression of GATA3 decrease significantly in BC patients than control (Odd ratio 2.55, 95% CI 1.45-2.37, P=0.0001), On the other hand, the positivity of GATA3 protein increased significantly in patients with invasive ductal carcinoma (IDC) (P=0.001). Keyword: GATA3, Breast Cancer, Immunohistochemical Expression.
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Kailasam, Karthik, Mohammad Omaira, Hardik Satish Chhatrala, and Marie Ravichandar. "Prognostic implication of GATA3 gene mutation on survival in invasive ductal carcinoma of the breast." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13114-e13114. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13114.
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e13114 Background: GATA3 encodes a transcription factor, which is involved in activation and suppression of genes involved in cell maturation. GATA3 is necessary in the adult mammary gland to maintain the integrity and function of the luminal epithelium. Methods: METABRIC project funded by cancer research UK, the British Columbia cancer foundation and the Canadian breast cancer foundation mapped 173 gene mutations and amplifications in 2,433 primary breast tumors. Retrospective analysis was done for patients with invasive ductal carcinoma of the breast in the age group 30-60; to study the effect of GATA3 mutation on survival. Median survival was obtained from Kaplan-Meier plot, and mortality between groups was compared by Odds ratio (OR). Results: A total of 1500 patients across all age groups had invasive ductal carcinoma. 650 were within the age group 30-60; of which 234 died due to the disease, 360 were alive and 55 died due to other causes. 398 patients (61.2%) tested positive for estrogen receptor (ER) and 521 patients (80.2%) were negative for HER2 (human epidermal growth factor receptor 2). TP53 (50%) and PIK3CA (36%) mutations were more prevalent. GATA3 mutation was found in 79 patients (12.34%); among which, all 79 patients tested positive for ER (100%) and 74 patients (94.9%) negative for HER2. 10 patients (12.7%) died due to the disease, 62 patients (78.5%) were alive and 7 patients (8.9%) died due to other causes. Hence, patients with GATA3 mutations were more likely to survive (OR 4.66; CI 2.33-9.29 p < 0.0001) than patients without the mutation. The median survival for patients with GATA3 mutation (300 months) was also greater than patients without the mutation (219 months). In addition, patients with GATA3 mutation were more likely to be ER positive and HER2 negative. Conclusions: In the mammary gland, GATA3 is required for luminal epithelial cell differentiation. Loss of GATA3 results in de-differentiation to stem cell phenotype. It is found that GATA3 mutation correlates with a better prognosis compared to more common TP53 and PIK3CA gene mutations.
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Krendl, Christian, Dmitry Shaposhnikov, Valentyna Rishko, Chaido Ori, Christoph Ziegenhain, Steffen Sass, Lukas Simon, et al. "GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency." Proceedings of the National Academy of Sciences 114, no. 45 (October 25, 2017): E9579—E9588. http://dx.doi.org/10.1073/pnas.1708341114.
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To elucidate the molecular basis of BMP4-induced differentiation of human pluripotent stem cells (PSCs) toward progeny with trophectoderm characteristics, we produced transcriptome, epigenome H3K4me3, H3K27me3, and CpG methylation maps of trophoblast progenitors, purified using the surface marker APA. We combined them with the temporally resolved transcriptome of the preprogenitor phase and of single APA+ cells. This revealed a circuit of bivalent TFAP2A, TFAP2C, GATA2, and GATA3 transcription factors, coined collectively the “trophectoderm four” (TEtra), which are also present in human trophectoderm in vivo. At the onset of differentiation, the TEtra factors occupy multiple sites in epigenetically inactive placental genes and in OCT4. Functional manipulation of GATA3 and TFAP2A indicated that they directly couple trophoblast-specific gene induction with suppression of pluripotency. In accordance, knocking down GATA3 in primate embryos resulted in a failure to form trophectoderm. The discovery of the TEtra circuit indicates how trophectoderm commitment is regulated in human embryogenesis.
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Labastie, M. C., D. Bories, C. Chabret, J. M. Grégoire, S. Chrétien, and P. H. Roméo. "Structure and Expression of the Human GATA3 Gene." Genomics 21, no. 1 (May 1994): 1–6. http://dx.doi.org/10.1006/geno.1994.1217.
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Syrkasheva, Anastasiya G., Nataliya V. Dolgushina, Andrey Yu Romanov, Olga V. Burmenskaya, Nataliya P. Makarova, Espet O. Ibragimova, Elena A. Kalinina, and Gennady T. Sukhikh. "Cell and genetic predictors of human blastocyst hatching success in assisted reproduction." Zygote 25, no. 5 (September 20, 2017): 631–36. http://dx.doi.org/10.1017/s0967199417000508.
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SummaryThe aim was to identify cell and genetic predictors of human blastocyst hatching success in assisted reproduction programmes via a prospective case–control study. Blastocysts, donated by couples in assisted reproduction programmes were used. Hatching success assessment was performed after 144–146 h post-fertilization. The mRNA expression levels of cathepsin V (CTSV), GATA-binding protein 3 (GATA3) and human chorionic gonadotropin beta subunit 3, 5, 7 and 8 (CGB) genes were detected by quantitative real-time polymerase chain reaction. The odds ratio (OR) of hatching due to zona pellucida (ZP) thickness, oocyte and sperm quality, embryo quality and mRNA expression of CTSV, GATA3 and CGB genes in blastocysts was determined. From 62 blastocysts included in the study, 47 (75.8%) were unable to hatch spontaneously. The ZP thickening, and oocyte and sperm quality did not affect human blastocyst ability to hatch, except the combination of cytoplasmic and extracytoplasmic oocyte dysmorphisms (OR = 1.25; 95% confidence interval = 1.08, 1.45). Hatching-capable blastocysts had higher Gardner scale grade and mRNA expression of CTSV, GATA3 and CGB genes than hatching-incapable blastocysts. The human blastocyst hatching success depends on the blastocyst Gardner grade, but not on ZP and gamete quality. Blastocyst development was regulated by CTSV, GATA3 and CGB gene expression.
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Takaku, Motoki, Sara A. Grimm, Bony De Kumar, Brian D. Bennett, and Paul A. Wade. "Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3." Nucleic Acids Research 48, no. 9 (March 30, 2020): 4756–68. http://dx.doi.org/10.1093/nar/gkaa179.
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Abstract Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.
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Onodera, Atsushi, Masakatsu Yamashita, Yusuke Endo, Makoto Kuwahara, Soichi Tofukuji, Hiroyuki Hosokawa, Akinori Kanai, Yutaka Suzuki, and Toshinori Nakayama. "STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells." Journal of Experimental Medicine 207, no. 11 (October 18, 2010): 2493–506. http://dx.doi.org/10.1084/jem.20100760.
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Polycomb group (PcG) and trithorax group (TrxG) complexes exert opposing effects on the maintenance of the transcriptional status of the developmentally regulated Hox genes. In this study, we show that activation of STAT6 induces displacement of the PcG complex by the TrxG complex at the upstream region of the gene encoding GATA3, a transcription factor essential for T helper type 2 (Th2) cell differentiation. Once Th2 cells differentiate, TrxG complex associated with the TrxG component Menin binds to the whole GATA3 gene locus, and this binding is required for the long-term maintenance of expression of GATA3 and Th2 cytokine. Thus, STAT6-mediated displacement of PcG by the TrxG complex establishes subsequent STAT6-independent maintenance of GATA3 expression in Th2 cells via the recruitment of the Menin–TrxG complex.
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Grigorieva, Irina V., Andre Oszwald, Elena F. Grigorieva, Helga Schachner, Barbara Neudert, Tammo Ostendorf, Jürgen Floege, et al. "A Novel Role for GATA3 in Mesangial Cells in Glomerular Development and Injury." Journal of the American Society of Nephrology 30, no. 9 (August 12, 2019): 1641–58. http://dx.doi.org/10.1681/asn.2018111143.
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BackgroundGATA3 is a dual-zinc finger transcription factor that regulates gene expression in many developing tissues. In the kidney, GATA3 is essential for ureteric bud branching, and mice without it fail to develop kidneys. In humans, autosomal dominant GATA3 mutations can cause renal aplasia as part of the hypoparathyroidism, renal dysplasia, deafness (HDR) syndrome that includes mesangioproliferative GN. This suggests that GATA3 may have a previously unrecognized role in glomerular development or injury.MethodsTo determine GATA3’s role in glomerular development or injury, we assessed GATA3 expression in developing and mature kidneys from Gata3 heterozygous (+/−) knockout mice, as well as injured human and rodent kidneys.ResultsWe show that GATA3 is expressed by FOXD1 lineage stromal progenitor cells, and a subset of these cells mature into mesangial cells (MCs) that continue to express GATA3 in adult kidneys. In mice, we uncover that GATA3 is essential for normal glomerular development, and mice with haploinsufficiency of Gata3 have too few MC precursors and glomerular abnormalities. Expression of GATA3 is maintained in MCs of adult kidneys and is markedly increased in rodent models of mesangioproliferative GN and in IgA nephropathy, suggesting that GATA3 plays a critical role in the maintenance of glomerular homeostasis.ConclusionsThese results provide new insights on the role GATA3 plays in MC development and response to injury. It also shows that GATA3 may be a novel and robust nuclear marker for identifying MCs in tissue sections.
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Gaynor, Katherine U., Irina V. Grigorieva, M. Andrew Nesbit, Treena Cranston, Thushari Gomes, Ludwig Gortner, and Rajesh V. Thakker. "A Missense GATA3 Mutation, Thr272Ile, Causes the Hypoparathyroidism, Deafness, and Renal Dysplasia Syndrome." Journal of Clinical Endocrinology & Metabolism 94, no. 10 (October 1, 2009): 3897–904. http://dx.doi.org/10.1210/jc.2009-0717.
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Context: The hypoparathyroidism, deafness, renal dysplasia (HDR) syndrome is caused by mutations in the gene encoding GATA3, which belongs to a family of dual zinc-finger transcription factors that have a role in vertebrate embryonic development. Objective: The aim of the study was to identify the GATA3 mutation in a HDR patient and determine its functional consequences. Patient and Design: A patient with HDR was studied after approval from the local ethical committee. Leukocyte DNA was used with GATA3-specific primers for PCR amplification, and the DNA sequences of the PCR products were determined. Wild-type and mutant GATA3 constructs were transfected into COS-7 cell, and their functions were assessed by Western blot analysis, immunocytochemistry, EMSAs, luciferase reporter assays, and three-dimensional modeling. Results: A novel missense mutation, Thr272Ile, in zinc finger 1 (ZnF1) of GATA3 was identified. Western blot analysis and immunofluorescence revealed that the mutation did not affect nuclear localization of GATA3. However, EMSAs showed it to reduce DNA binding affinity, but not stability, and yeast two-hybrid assays demonstrated that the mutant GATA3 resulted in a loss of interaction with ZnF1 and ZnF6 of the cofactor FOG2. The mutant GATA3 significantly reduced luciferase reporter activity by more than 65% (P < 0.001), and three-dimensional modeling indicated that the functional abnormalities may be due to a loss of Thr272 polar side chain interaction with Leu268. Conclusions: A novel missense HDR-associated GATA3 mutation, Thr272Ile, has been identified and shown to result in reduced DNA binding, a partial loss of FOG2 interaction, and a decrease in gene transcription. Hypoparathyroidism, Deafness, and Renal Dysplasia syndrome can result from the missense mutation Thr272Il3 in the transcription factor GATA3, which results in reduced DNA binding, partial loss of interaction with the protein cofactor FOG2, and a decrease in transcriptional activity.
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Ono, Yuichi, Norio Fukuhara, and Osamu Yoshie. "TAL1 and LIM-Only Proteins Synergistically Induce Retinaldehyde Dehydrogenase 2 Expression in T-Cell Acute Lymphoblastic Leukemia by Acting as Cofactors for GATA3." Molecular and Cellular Biology 18, no. 12 (December 1, 1998): 6939–50. http://dx.doi.org/10.1128/mcb.18.12.6939.
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ABSTRACT Previously, we have shown that TAL1 and the LIM-only protein gene (LMO) are regularly coactivated in T-cell acute lymphoblastic leukemia (T-ALL). This observation is likely to relate to the findings that TAL1 and LMO are highly synergistic in T-cell tumorigenesis in double-transgenic mice. To understand the molecular mechanisms of functional synergy between TAL1 and LMO in tumorigenesis and transcriptional regulation, we tried to identify downstream target genes regulated by TAL1 and LMO by a subtractive PCR method. One of the isolated genes, that for retinaldehyde dehydrogenase 2 (RALDH2), was regularly expressed in most of the T-ALL cell lines that coexpressed TAL1 and LMO. Exogenously transfected TAL1 and LMO, but not either alone, inducedRALDH2 expression in a T-ALL cell line, HPB-ALL, not expressing endogeneous TAL1 or LMO. The RALDH2 transcripts in T-ALL were, however, mostly initiated within the second intron. Promoter analysis revealed that a GATA site in a cryptic promoter in the second intron was essential and sufficient for the TAL1- and LMO-dependent transcriptional activation, and GATA3 binds to this site. In addition, forced expression of GATA3 potentiated the induction ofRALDH2 by TAL1 and LMO, and these three factors formed a complex in vivo. Furthermore, a TAL1 mutant not binding to DNA also activated the transcription of RALDH2 in the presence of LMO and GATA3. Collectively, we have identified the RALDH2 gene as a first example of direct transcriptional target genes regulated by TAL1 and LMO in T-ALL. In this case, TAL1 and LMO act as cofactors for GATA3 to activate the transcription ofRALDH2.
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Negrón-Pérez, Verónica M., Yanping Zhang, and Peter J. Hansen. "Single-cell gene expression of the bovine blastocyst." Reproduction 154, no. 5 (November 2017): 627–44. http://dx.doi.org/10.1530/rep-17-0345.
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The first two differentiation events in the embryo result in three cell types – epiblast, trophectoderm (TE) and hypoblast. The purpose here was to identify molecular markers for each cell type in the bovine and evaluate the differences in gene expression among individual cells of each lineage. The cDNA from 67 individual cells of dissociated blastocysts was used to determine transcript abundance for 93 genes implicated as cell lineage markers in other species or potentially involved in developmental processes. Clustering analysis indicated that the cells belonged to two major populations (clades A and B) with two subpopulations of clade A and four of clade B. Use of lineage-specific markers from other species indicated that the two subpopulations of clade A represented epiblast and hypoblast respectively while the four subpopulations of clade B were TE. Among the genes upregulated in epiblast were AJAP1, DNMT3A, FGF4, H2AFZ, KDM2B, NANOG, POU5F1, SAV1 and SLIT2. Genes overexpressed in hypoblast included ALPL, FGFR2, FN1, GATA6, GJA1, HDAC1, MBNL3, PDGFRA and SOX17, while genes overexpressed in all four TE populations were ACTA2, CDX2, CYP11A1, GATA2, GATA3, IFNT, KRT8, RAC1 and SFN. The subpopulations of TE varied among each other for multiple genes including the prototypical TE marker IFNT. New markers for each cell type in the bovine blastocyst were identified. Results also indicate heterogeneity in gene expression among TE cells. Further studies are needed to confirm whether subpopulations of TE cells represent different stages in the development of a committed TE phenotype.
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Mosaad, Y. M., A. Hammad, A. A. Elghzaly, Z. M. E. Tawhid, E. M. Hammad, A. Showma, R. Abdelsalam, A. Elmoughy, I. M. Fawzy, and N. Anber. "GATA3 rs3824662 gene polymorphism as possible risk factor for systemic lupus erythematosus." Lupus 27, no. 13 (October 9, 2018): 2112–19. http://dx.doi.org/10.1177/0961203318804894.
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Background There is no report about the association between GATA3 rs3824662 polymorphism and systemic lupus erythematosus (SLE). Objective To investigate the possible role of GATA3 rs3824662 polymorphism as a susceptibility risk factor for either adult SLE (aSLE) or pediatric SLE (pSLE) and to evaluate its role in the development of lupus nephritis (LN) in pSLE. Methods Typing of GATA3 rs3824662 polymorphism was done using real-time polymerase chain reaction for three groups; 104 pSLE patients, 140 aSLE patients and 436 age- and sex-matched healthy controls. Results Non-significant differences were found between SLE patients and healthy controls for the allele and genotype frequencies of GATA3 rs3824662 ( p > 0.05). In pSLE; the AC genotype was associated with LN ( p = 0.04); the A allele and AC genotype were associated with persistent proteinuria ( p = 0.036 and 0.01, respectively) and both the A allele and AA genotype were associated with higher chronicity index ( p = 0.031 and 0.04, respectively). In aSLE; the C allele was associated with cellular cast ( p = 0.03) and thrombocytopenia ( p = 0.01). Logistic regression analysis revealed significant association between the AC+AA genotypes and the prediction of LN and renal active disease in pSLE ( p = 0.04 and 0.01, respectively). Conclusion GATA3 rs3824662 is not associated with susceptibility to SLE either in adult or in pediatric patients; however, in pSLE patients, the heterozygous AC genotype could be considered a risk factor for LN. At the same time, the AC and AA genotypes could be considered as predictors for LN and active renal disease. However, the small sample size is a limiting factor of the present study when interpreting the positive association.
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Parinaz, Mehdipour, Tavasoli Manoochehr, Faghihi Mehri, Safari Forouzan, and Babazadeh Shadi. "Mutations of GATA3 gene in breast cancer patients." Clinical Biochemistry 44, no. 13 (September 2011): S196. http://dx.doi.org/10.1016/j.clinbiochem.2011.08.478.
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Xu, Wei, and Barbara L. Kee. "Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas." Blood 109, no. 10 (February 1, 2007): 4406–14. http://dx.doi.org/10.1182/blood-2006-08-043331.
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AbstractThe E2A transcription factors are required for normal T lymphopoiesis and to prevent T-lymphocyte progenitor transformation. Ectopic expression of E2A proteins in E2A-deficient lymphomas results in growth arrest and apoptosis, indicating that these cells remain responsive to the targets of E2A. Here we identify the transcriptional repressor growth factor independent 1B (Gfi1b) as a target of E2A that promotes growth arrest and apoptosis in lymphomas. Gfi1b expression in primary T-lymphocyte progenitors is dependent on E2A and excess Gfi1b prevents the outgrowth of T lymphocyte progenitors in vitro. Gfi1b represses expression of Gata3, a transcription factor whose appropriate regulation is required for survival of lymphomas and T-lymphocyte progenitors. We also show that ectopic expression of Gata3 in lymphomas promotes expression of Gfi1b, indicating that these proteins may function in an autoregulatory loop that maintains appropriate levels of Gata3. Therefore, we propose that E2A proteins prevent lymphoma cell expansion, at least in part through regulation of Gfi1b and modulation of Gata3 expression.
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Lage, Luis Alberto de Padua Covas, Claudio Vinicius Brito, Debora Levy, Hebert Fabricio Culler, Samuel Campanelli Freitas Couto, Lucas BO Alves, Maria C. Zerbini, Vanderson Rocha, and Juliana Pereira. "GATA3 Gene - a Potential New Biomarker Associated with Adverse Outcomes in ALK1-Negative Anaplastic Large Cell Lymphoma: Preliminary Results from a Retrospective Cohort of 80 South American Cases of Nodal Peripheral T Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 38. http://dx.doi.org/10.1182/blood-2020-140833.
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Introduction: Nodal peripheral T-cell lymphomas (nPTCLs) comprise a heterogeneous group of mature and aggressive T-cell lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphomas (ALCL) ALK1-positive and ALK1-negative. The differential diagnosis of nPTCL can be very challenging in clinical practice and it has a markedly heterogeneous prognosis. Accurate biomarkers to distinguish the different histological subtypes of nPTCL and to stratify its prognosis are essential to improve the therapeutic approach. The aim of this study was to assess the prognostic impact of GATA3 gene expression, as well as its ability to discriminate between different histopathological subtypes of nPTCLs. Methods: In this observational, retrospective and single-center study, we analyzed clinical-epidemiological data, outcomes and molecular characteristics of 80 nPTCL patients treated at the largest Brazilian cancer center from January 2000 to December 2017. Analysis of GATA3 gene expression was assessed by quantitative real-time polimerase chain reaction (qRT-PCR) of tumor tissue biopsies fixed in formalin and embedded in paraffin (FFPE) at the time of diagnosis. The association of relative expression of the GATA3 gene with pathological variants of nPTCL was determined by the Kruskal-Wallis test and the Dunn's post-hoc test. The cutoff value of GATA3 expression capable of differentiating nPTCLs variants was determined by constructing receiver-operator-characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Results: The clinical and epidemiological characteristics of the 80 nPTCL patients are summarized in Table 1. Median age was 49 years (IqR 34-59), 43-80 (53.7%) of patients were male. Of these, 36.3% were classified as PTCL-NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. Most of the cases had an advanced stage (III and IV Ann Arbor). With a median follow-up of 1.72 years, the estimated OS at 2 years and PFS were 52.2% and 39.5%, respectively. The median level of GATA3 gene expression was 0.49% (range 0 - 7.07%) in the global cohort, being 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL, NOS and 0.67% for AITL. The difference in expression of the GATA3 gene between different nPTCL variants was statistically significant (p <0.001) - Figure 1. The levels of expression of the GATA3 gene ≥ 0.71% discriminated PTCL, NOS from ALK-negative ALCL and AITL with a sensitivity of 62% and specificity of 80.3%, contributing to the differential diagnosis of these neoplasms, particularly in cases of ALK-negative ALCL versus PTCL, NOS CD30-positive. Overexpression of GATA3 ≥ median was associated with poor 2-year OS for PTCL, NOS (46.7% x 21.4%, p = 0.04) and for ALK-negative ALCL (85.7% x 54.5%, p = 0.04) - Figures 2 and 3. Conclusion: Despite the relatively small number of patients in our cohort, preliminary results suggest that overexpression of the GATA3 gene may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Our results corroborate the findings of Iqbal et al, 2014, reinforcing the adverse prognostic impact of GATA3 gene expression in PTCL/NOS, and we show that its overexpression may be a potential novel biomarker related to poor prognosis for ALK-negative ALCL. In addition, it has been demonstrated here that GATA3 can play an auxiliary role in discriminating different subtypes of nPTCLs, aiding the differential diagnosis of these neoplasms, which often have overlapping clinical and pathological aspects. Other studies with larger series of patients should confirm our findings. Disclosures No relevant conflicts of interest to declare.
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Fransecky, Lars, Martin Neumann, Sandra Heesch, Marco Seehawer, Cornelia Schlee, Liliana H. Mochmann, Stefan Schwartz, Nicola Goekbuget, Dieter Hoelzer, and Claudia D. Baldus. "GATA3 Silencing Defines a Distinct Subset of ETP-ALL." Blood 120, no. 21 (November 16, 2012): 2389. http://dx.doi.org/10.1182/blood.v120.21.2389.2389.
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Abstract Abstract 2389 Introduction The transcription factor GATA3 plays an important role in normal T cell development. Its role in mature T cells is well understood, but its function in earlier stages of T cell development remains unclear. Whereas GATA3 levels are precisely regulated for the T cell differentiation program, aberrant expression of GATA3 has been linked to tumorigenesis. Based on these observations, we investigated the role of GATA3 in Early Thymic Progenitor Acute Lymphoblastic Leukemia (ETP-ALL), a newly defined high-risk subgroup of T-ALL, characterized by a specific gene expression profile and distinct immunophenotype. Patients and Methods Eighty-six bone marrow samples from adult patients with newly diagnosed T-ALL, including ETP-ALL (n=17) enrolled into the German Multicenter Acute Lymphoblastic Leukemia (GMALL) trials, were studied for GATA3 expression by oligonucleotide expression arrays (HG-U133 plus 2.0) within the Microarray Innovations in LEukemia study. We identified additional 71 ETP-ALL adult patients and 94 T-ALL patients enrolled on the GMALL protocol, in which GATA3 mRNA expression was measured by quantitative polymerase chain reaction (RT-PCR). Combining ETP-ALL and T-ALL cases (n=165), we defined two GATA3 expression groups GATA3null and GATA3high based on a biological gap (GATA3 expression of 0.2). DNA methylation was analyzed in both T-ALL (n=11) and ETP-ALL (n=69) samples by pyrosequencing with primers designed to include seven CpG sites of Exon 2/Intron 3 of GATA3. Samples were grouped into GATA3 high vs. low methylation according to their mean methylation being below or above 40%. Results Based on gene expression arrays we observed a high proportion of ETP-ALL (11/17) that lacked GATA3 expression, whereas only a small fraction of the remaining T-ALL cases (3/69) had no GATA3 expression. These results were validated by RT-PCR in a larger cohort: 26% of ETP-ALL (19/71) were GATA3null, but only 2% of T-ALL (2/94) were in the GATA3null expression group. To explore the regulation of this specific expression pattern, epigenetic regulation of GATA3 was analyzed by pyrosequencing. While unselected T-ALL samples were hypomethylated (< 6% methylated CpG), ETP-ALL samples had a higher GATA3 methylation status (28% methylated CpG, p<0.001). ETP-ALL cases were further categorized into high methylated (18/69) and low methylated samples (51/69) and correlated to mRNA expression. GATA3null samples showed a higher degree of GATA3 methylation (41% methylated CpGs) compared to GATA3high samples (8% methylated CpGs, p < 0.001). In an in-vitro assay of T-cell leukemia cell lines demethylating agents increased GATA3 mRNA expression by up to 5-fold. In murine hematopoetic stem cells it was shown that loss of DNMT3A induced GATA3 expression via hypomethylation. In ETP-ALL, we identified 11 DNMT3A mutations in 69 samples (16%) and correlated the DNMT3A mutation status to GATA3 methylation. Ten of 11 (91%) DNMT3A mutated samples showed low level GATA3 methylation, whereas 17 (29%) of the 58 DNMT3A wildtype cases had high methylation. Conclusion ETP-ALL is a subgroup of adult T-ALL with a distinct molecular profile. Here we show that within ETP-ALL a separate molecular entity can be defined by GATA3 silencing due to DNA methylation. In-vitro studies showed that GATA3 expression can be restored by the use of demethylating agents. As loss of function mutations in DNMT3A correlate with low GATA3 methylation in ETP-ALL, a potential role of DNMT3A in the epigenetic silencing of GATA3 is suspected. So far, the number of targeted drugs available for T-ALL is limited. Therefore, incorporating demethylating agents may resolve the T-cell differentiation block in T-ALL by increasing GATA3 expression. Future work will explore downstream effects of GATA3 in acute leukemia. Disclosures: No relevant conflicts of interest to declare.
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Maura, Francesco, Luca Agnelli, Anna Dodero, Javeed Iqbal, Niccolo Bolli, Cristiana Carniti, Tayla Heavican, et al. "Peripheral T-Cell Lymphomas Not Otherwise Specified: Potential Novel Molecular Entities Based on Both Tumor and Microenvironment Cellular Components." Blood 128, no. 22 (December 2, 2016): 4098. http://dx.doi.org/10.1182/blood.v128.22.4098.4098.
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Abstract INTRODUCTION: The diagnosis of Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS) is currentlybased on an "exclusion criteria" model, since PTCL-NOS lack pathognomonic features. Nevertheless, based on gene expression data, Iqbal et al(Blood 2014) have recently identified two different PTCL-NOS subgroups with different biological and prognostic features that accounts for approximately 80% of the cases and have different biological and prognostic features: one characterized by TBX21 overexpression and T-CD8+ molecular profile; the other by GATA3 overexpression and T-CD4+ profile. Herein, we used a wide comprehensive gene expression profiling (GEP) data set in order to further investigate the molecular features of different PTCL-NOS molecular entities. MATHERIAL AND METHODS: A data set were created including samples from 8 main published series (GSE6338, GSE14879, GSE19067, GSE19069, GSE58445 and GSE65823 at http://www.ncbi.nlm.nih.gov/geo/; E-TABM-702 and E-TABM-783 at https://www.ebi.ac.uk/arrayexpress) for a total of 541 patients. R/Bioconductor was used to generate and analyze the gene expression data. We applied the CIBERSORT algorithm (Gentles et al, Nat Gen 2015), which connects specific global expression profiles to the relative prevalence of tissue components (tumour and microenvironment cells). RESULTS: We first re-classified each sample included in the investigated data set based on previously published signatures (Iqbal et al. Blood 2014, Agnelli et al. Blood 2012). This approach led to a final data set of 144 PTCL-NOS (28%), 127 AITL (23%), 69 ALCL Alk neg (12%), 56 ALCL Alk pos (10%), 59 NK (11%) %), together with 86 healthy T-cell tissues. To our knowledge, this is the largest GEP data set ever described in PTCL so far. In the 144 PTCL-NOS cases, two main molecular clusters were extracted based on published signature, replicating previous findings: the first was characterized by both GATA3 expression (GATA3+) and T-CD4+ cell origin; the second by TBX21 expression (TBX21+) and T-CD8+ cell origin. Approximately 30% of all PTCL-NOS were characterized by neither GATA3 (GATA-) nor TBX21 expression (TBX21-), and for this reason they were classified as "double negative" PTCL-NOS. Based on data obtained by the CIBERSORT algorithm we found that the contribution of cellular microenvironment components was extremely heterogeneous and variable through the entire PTCL-NOS series. A significant T-CD4+ and T-CD8+ cell enrichment was reported among GATA3+ and TBX21+ groups, respectively. Interestingly, a fraction of GATA3+ PTCL-NOS (n=11, 7.6%) was characterized by a significant γδ T-cell component. Conversely, PTCL-NOS GATA3+ patients without γδ T-cell component signature were characterized by a low non-T-cell microenvironment component. This may reflect the major tumour infiltration due to higher proliferation rate as suggested by the strong GATA3 correlation with MIB1 and MYC expression (p<0.0001 and p=0.01, respectively). PTCL-NOS TBX21+/GATA3- were mainly divided into two different groups: the first characterized by strong plasma cell enrichment and the second by major macrophage contribution. "Double-negative" PTCL-NOS (n=38) were generally characterized by strong T-follicular helper (T-FH) and B-cell signatures contribution. Based on the clinical data available for 105/144 PTCL-NOS, poor overall survival (OS) was associated with GATA3 expression (p=0.03) [3-y OS 26.4% (range 20-32.8%) vs 47.3% (range 40-54.5%)]. However, such a poor outcome was less evident when we limited the clinical evaluation to patients younger than 60 years (40/105). Among low GATA3 expressors, TBX21 expression was associated with better OS compared to other "double negative" PTCL-NOS (p=0.07) [3-y OS 66.7% (range 51-82.4%) vs 36.4% (range 22-51%)]. Higher CIBERSORT-predicted T-CD8+ contribution was associated with better OS among patients younger than 60 years (p=0.03) [3-y OS 70% (range 55.6-84.5%) vs 30% (range 21.7-38.3%)]. No other variables or clusters were associated with significant impact on OS. CONCLUSION: Our study based on an innovative computational approach and a large and comprehensive gene expression data set, confirmed the great molecular heterogeneity of PTCL-NOS, suggesting that the current molecular classification of PTCL-NOS may be further improved in the future. Disclosures No relevant conflicts of interest to declare.
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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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Gilli, Simone C. O., Tereza S. I. Salles, and Sara Saad. "Regulation of the GATA3 Promoter by Human T-Cell Lymphotropic Virus Type I Tax Protein." Blood 104, no. 11 (November 16, 2004): 4309. http://dx.doi.org/10.1182/blood.v104.11.4309.4309.
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Abstract The HTLV-I nonstructural protein Tax plays a crucial role in cellular transformation. It activates the transcription factors of various cellular genes and interacts with cellular proteins. There is limited data available on the interaction between specific T cell transcription factor GATA3 and Tax. Implications for the significance of GATA3 in T-cell development and function, (Th2) differentiation, and a role of GATA3 during the immune response have been reported. We had previously demonstrated decreased GATA3 mRNA expression in HTLVI infected individuals and in patients with ATLL and HAM/TSP [Gilli et al., 2000]. To determine the effect of the Tax protein on GATA3 gene expression, we investigated the interaction between this protein and its promoter and repressor regions by DNA-protein interaction and “in vitro” transcription assays. Results demonstrated an interaction between Tax and the GATA3 promoter via the transcription factor Sp1 and a role for Tax in the negative regulation of GATA3 expression, through its interaction with the repressor ZEB. This interaction may be involved in the pathophysiology of adult T cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy.
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Madzio, Joanna, Agata Pastorczak, Marcin Braun, Joanna Taha, Kamila Wypyszczak, Michal Matysiak, Jerzy Kowalczyk, et al. "Polymorphic Variant in GATA3 gene Is a Hallmark of PAR1-Deleted BCP-ALL and Associates with Poor Prognosis Among Pediatric Patients Treated with the BFM Backbone Protocols." Blood 128, no. 22 (December 2, 2016): 1742. http://dx.doi.org/10.1182/blood.v128.22.1742.1742.
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Abstract Introduction Germline variant at rs3824662 in GATA3 gene was associated with early response to treatment as well as relapse risk in childhood BCP-ALL treated with COG protocols. This effect resulted from the strong link between the GATA3 polymorphism and the presence of somatic defects in leukemic cells including IKZF1 deletions, CRLF2 rearrangements and JAK2 gene mutations, which promote aggressive course of the disease. Aims The study aimed to evaluate an association between GATA3 gene polymorphism and clinical and biological features of pediatric BCP-ALL treated with the BFM backbone protocols. Methods Between November 2010 and June 2016, 957 consecutive children with newly diagnosed BCP-ALL were enrolled into the study. 822 patients treated according to ALL-IC BFM2009 protocol (n=594) and ALL-IC BFM2002 protocol (n=228) in 15 centers of the Polish Pediatric Leukemia/Lymphoma Study Group were enrolled into the study (median age 4.5 yrs, median follow-up time 2.5 yrs). Patients with BCR-ABL1 and MLL gene rearrangements were excluded from the analysis. The rs3824662 polymorphism of the GATA3 gene was genotyped using TaqMan probes. GATA3 mRNA expression level in leukemic cell was evaluated in BCP-ALL cases using qPCR with FAM-MGB probes (n=136). Targeted copy number screening of selected 23 loci was performed using the P335-B2 SALSA MLPA kit (MRC-Holland, Netherlands) in n=807 available DNA leukemia samples. MRD at day 15 and 33 was measured by flow cytometry with EuroFlow 8-color antibody panels. Results In the study group genotypes distribution withinrs3824662 of GATA3 was as follows: AA: n=44 (5.4%); CA: n=266 (32.4%); CC: n=512 (62.3%). Median MRD15 and MRD33 were 0.31% and 0.001% respectively. IKZF1 deletion were found in 18%, PAX5 in 20%, PAR1 in 12%, CDKN2A in 24%, CDKN2B 20%, BTG1 in 6.3%, ETV6 in 21%, EBF1 in 4% and RB1 in 6% of cases. Leukemic cells harbouring AA variant withinrs3824662 showed GATA3 mRNA expression 1.6 and 2.2 times higher compared to cells with CA and CC variants respectively, with the difference close to significant (ANOVA p=0.06). The presence of AA variant was not related to any gene deletion apart from microdeletions of the pseudoautosomal region PAR1 (Xp22 and Yp11) which occurred more frequently in AA carriers as compared to CA and CC carriers (11/41 vs. 34/242 vs. 52/468, p=0.013). We did not find any association of clinical features such as initial WBC, steroid response, sex and age at diagnosis among BCP-ALL patients with GATA3 genotype. However, AA carriers had a higher risk for MRD>10% at day 15 OR (95%CI)=3.93 (1.37-11.23) as well as MRD>0.01% at day 33, OR(95%CI)=2.95 (1.12-7.73) as compared CC carriers. Cox model of survival analysis was done for variables with univariate significance of p<0.15 (risk group, sex). The results of Cox regression showedthe AA genotype remained associated with an increased risk of death regardless of risk group (assigned based on ALL-IC BFM09 protocol), HR(95%C)=2.95(1.12-7.73), P=0.028). Conclusions We showed that carriers of AA genotype in GATA3 are prone to develop PAR1 -deleted BCP-ALL. Moreover our study confirmed an association of GATA3 AA rs3824662 homozygosity with poor early response to treatment as well as risk of death among pediatric BCP-ALL patients treated with the BFM backbone protocols. Disclosures Madzio: National Science Centre: Research Funding.
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Kasal, Darshan N., Zhitao Liang, Maile K. Hollinger, Crystal Y. O’Leary, Wioletta Lisicka, Anne I. Sperling, and Albert Bendelac. "A Gata3 enhancer necessary for ILC2 development and function." Proceedings of the National Academy of Sciences 118, no. 32 (August 5, 2021): e2106311118. http://dx.doi.org/10.1073/pnas.2106311118.
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The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.
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Han, Songyan, Jun Lu, Yu Zhang, Cao Cheng, Liping Han, Xiuli Wang, Lin Li, Chunyan Liu, and Baiqu Huang. "Recruitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription." Biochemical Journal 400, no. 3 (November 28, 2006): 439–48. http://dx.doi.org/10.1042/bj20061085.
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The critical role of IL-5 (interleukin-5) in eosinophilic inflammation implicates it as a therapeutic target for allergic diseases. The aim of the present study was to elucidate the molecular basis for the involvement of reversible histone acetylation in IL-5 transcriptional regulation. We provide evidence that HDAC4 (histone deacetylase 4) and p300, a known HAT (histone acetyltransferase), reversibly controlled the activity of the IL-5 promoter in vivo and in vitro, with a concurrent alteration of histone H3 acetylation status at the promoter regions. The nucleo-cytoplasmic shuttling of HDAC4 was shown to play an important role in the suppressive function of HDAC4 in IL-5 gene expression. Point mutation and reporter ChIP (chromatin immunoprecipitation) studies determined that the four transcription factors binding on the IL-5 promoter, i.e. C/EBPβ (CAAT/enhancer-binding protein β), GATA3 (GATA binding protein 3), NFAT (nuclear factor of activated T cells) and YY1 (Yin and Yang 1), were essential for the recruitment of HDAC4. Consistent with these observations, HDAC4 was found to form protein complexes with GATA3 and YY1, and to co-exist in the nuclei with GATA3. We propose that the unique regulatory mechanism of IL-5 gene transcription involves the reversible histone modification catalysed by HDAC4 and p300, which are recruited by the transcription factors. The dynamic balance in IL-5 transcriptional regulation is achieved through interactions among HATs/HDACs, histones and transcription factors. These data contribute to understanding the molecular mechanisms of IL-5 regulation, which is crucial to the development of new therapeutic strategies for IL-5-related allergic diseases.
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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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Thakkar, Arvind, Hemanth Raj, Ravishankar, Bhaskaran Muthuvelan, Arun Balakrishnan, and Muralidhara Padigaru. "High Expression of Three-Gene Signature Improves Prediction of Relapse-Free Survival in Estrogen Receptor-Positive and Node-Positive Breast Tumors." Biomarker Insights 10 (January 2015): BMI.S30559. http://dx.doi.org/10.4137/bmi.s30559.
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The objective of the present study was to validate prognostic gene signature for estrogen receptor alpha-positive (ERα+) and lymph node (+) breast cancer for improved selection of patients for adjuvant therapy In our previous study, we identified a group of seven genes ( GATA3, NTN4, SLC7A8, ENPP1, MLPH, LAMB2, and PLAT) that show elevated messenger RNA (mRNA) expression levels in ERα (+) breast cancer patient samples. The prognostic values of these genes were evaluated using gene expression data from three public data sets of breast cancer patients ( n = 395). Analysis of ERα (+) breast cancer cohort ( n = 195) showed high expression of GATA3, NTN4, and MLPH genes significantly associated with longer relapse-free survival (RFS). Next cohort of ERα (+) and node (+) samples ( n = 109) revealed high mRNA expression of GATA3, SLC7A8, and MLPH significantly associated with longer RFS. Multivariate analysis of combined three-gene signature for ERα (+) cohort, and ERα (+) and node (+) cohorts showed better hazard ratio than individual genes. The validated three-gene signature sets for ERα (+) cohort, and ERα (+) and node (+) cohort may have potential clinical utility since they demonstrated predictive and prognostic ability in three independent public data sets.
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Li, Chunjie, Jiabi Qian, Chuang Jiang, Ziping LI, and Hui Zhang. "Inherited GATA3 Variants Associated with Positive Minimal Residual Disease in Childhood B-ALL Via Autophagy-Induced Asparaginase Resistance." Blood 134, Supplement_1 (November 13, 2019): 654. http://dx.doi.org/10.1182/blood-2019-123575.
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Accumulating evidence has confirmed that inherited genetic variations play multi-dimensional roles in childhood acute lymphoblastic leukemia (ALL), i.e., leukemia susceptibility, treatment response, chemotherapy tolerance, and relapse. Germline variants at the GATA3 locus increase the risk of developing Philadelphia chromosome-like ALL (Ph-like ALL) and inferior outcomes in childhood B-ALL among European and American cohorts. However, the role of inherited GATA3 variants in Han Chinese children with ALL still remains unclear. To primarily identify the association of inherited GATA3 variants with treatment response, we retrospectively collected 273 childhood B-ALL blood samples after complete remission was achieved according to the Chinese Childhood Cancer Group ALL 2015. We then genotyped rs3824662 and rs3781093 in the GATA3 locus. The risk allele frequencies of rs3824662 and rs3781093 were 35.7% and 36.3%, respectively, consistent with the 1000 Genomes Project. Using a logistic regression model, we correlated the GATA3 genotype with minimal residual disease (MRD) level. In our single center, we found that GATA3 rs3824662 A allele and rs3781093 C allele statistically associated with positive MRD (the cut-off was >=0.01%, P=0.046 and 0.038, respectively). The A allele in rs3824662 and C allele in rs3781093 linked to 2-fold increase in the risk of MRD compared with their wildtype allele. To explore the biological functions of these two germline SNP variants, we first utilized luciferase reporter assay to determine the impact of GATA3 variants on its transcription activity. Interestingly, the rs3824662 risk A allele significantly increased enhancer activity, while the rs3781093 did not show any effect. We next genetically modified rs3824662 from wild-type C allele to A allele in the lymphoblastoid cell GM12878 using clustered regularly interspaced short palindromic repeats/associated 9 (CRISPR/Cas9) gene editing system. Compared with wildtype GM12878 cells, ~3-folds higher GATA3 transcription level was found in GM12878 cells with A/A or A/C genotype. Integrating the high risk of MRD and upregulated GATA3 expression, we proposed that GATA3 rs3824662 A allele might contribute to poor treatment response by promoting GATA3 transcription. To clarify the association of GATA3 expression with the sensitivity of ALL chemotherapeutic drugs, we retrieved GSE653 and GSE654 expression data for analysis and found that high GATA3 expression significantly correlated with L-asparaginase (L-Asp) and daunorubicin (DNR) resistance. To further confirm the correlation, we ectopically overexpressed GATA3 in B-ALL cell line (Nalm6) and only L-asp resistance was validated. L-asp resistance induced by GATA3 over-expression was rescued by GATA3 interference, consolidating the association between GATA3 and L-asp resistance in B-ALL cells. Next, we probed the mechanism of GATA3-mediated L-asp resistance in B-ALL. We analyzed the association between inherited GATA3 variants and L-asp allergy, and did not identify statistical significance. Meanwhile, we couldn't find the correlation between GATA3 and ASNS, suggesting that ASNS might not be the cause either. Intriguingly, we found GATA3 over-expression induced the activation of autophagy-related genes, BECN1 and ATG5, which was reported to be associated with L-Asp resistance. Tests on primary B-ALL samples further confirmed this findings. To further confirm the effect of GATA3 on autophagy, we cloned highly conserved sequence BECN1 or ATG5 promoter region into luciferase reporter constructs. The Over-expression of GATA3 dramatically increased luciferase activity compared with the corresponding empty vector (P = 0.0098 and 0.0114, respectively), indicating that GATA3 expression were functionally activate their transcription. Taken together, all these data indicated that higher GATA3 expression might induce L-Asp resistance in B-ALL cells via autophagy activation. In conclusion, we first identified that GATA3 rs3824662 associated with the risk of MRD in the childhood ALL cohorts of Han ethnicity. Mechanistic study showed that inherited GATA3 variants possibly contributed to L-Asp resistance via autophagy activation induced by promoting GATA3 enhancer activity, providing new insights into the rationale for the future development of combinational treatment of L-Asp and anti-autophagy regimen in ALL patients. Figure Disclosures No relevant conflicts of interest to declare.
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Garcia-Perez, Laura, Farbod Famili, Martijn Cordes, Martijn Brugman, Marja van Eggermond, Haoyu Wu, Jihed Chouaref, et al. "Functional definition of a transcription factor hierarchy regulating T cell lineage commitment." Science Advances 6, no. 31 (July 2020): eaaw7313. http://dx.doi.org/10.1126/sciadv.aaw7313.
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T cell factor 1 (Tcf1) is the first T cell–specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell–committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.
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Hamburg, Jan Piet van, Marjolein J. W. de Bruijn, Claudia Ribeiro de Almeida, Gemma M. Dingjan, and Rudi W. Hendriks. "Gene expression profiling in mice with enforced Gata3 expression reveals putative targets of Gata3 in double positive thymocytes." Molecular Immunology 46, no. 16 (October 2009): 3251–60. http://dx.doi.org/10.1016/j.molimm.2009.08.004.
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Garcia-Rodriguez, Sonia, Jose-Luis Callejas-Rubio, Norberto Ortego-Centeno, Esther Zumaquero, Raquel Ríos-Fernandez, Salvador Arias-Santiago, Pilar Navarro, Jaime Sancho, and Mercedes Zubiaur. "Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients." Mediators of Inflammation 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/495934.
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Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin). Age- and gender-matched thirteen healthy controls were examined. AKT1 and MAPK1 expressions were upregulated in SLE patients and correlated with Th17-(Retinoic acid-related orphan receptor (ROR)-C), T-regulatory-(Treg)-(Transforming Growth Factor Beta (TGFB)-2), and Th2-(interleukin (IL)-5)-related genes. MAPK1 expression correlated with Th1-(IL-12A, T-box TF-(T-bet)), Th2-(GATA binding protein-(GATA)-3), and IL-10 expressions. IL-10 expression was increased and correlated with plasma Tumor Necrosis Factor (TNF)-αand Th0-(IL-2), Th1-(IL-12A, T-bet), GATA3, Treg-(Forkhead/winged-helix transcription factor- (FOXP)-3), and IL-6 expressions. FOXP3 expression, FOXP3/RORC, and FOXP3/GATA3 expression ratios were increased. Plasma IL-1β, IL-12(p70), Interferon-(IFN)-γ, and IL-6 cytokines were augmented. Plasma IL-1β, IL-6, IL-2, IFN-γ, TNF-α, IL-10, and IL-13 correlated with C-reactive protein, respectively. Increased Calprotectin correlated with neutrophils. Conclusion, SLE patients presented a systemic immunoinflammatory activity, augmented AKT1 and MAPK1 expressions, proinflammatory cytokines, and Calprotectin, together with increased expression of Treg-related genes, suggesting a regulatory feedback opposing the inflammatory activity.
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Ferraris, Silvio, Angelo Giovanni Del monaco, Emanuela Garelli, Adriana Carando, Barbara De Vito, Patrizia Pappi, Roberto Lala, and Alberto Ponzone. "HDR syndrome: A novel “de novo” mutation in GATA3 gene." American Journal of Medical Genetics Part A 149A, no. 4 (February 26, 2009): 770–75. http://dx.doi.org/10.1002/ajmg.a.32689.
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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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Wang, Tianjiao, Ye Lu, Avery Polk, Carlos Murga Zamalloa, and Ryan A. Wilcox. "Inhibition of IL2-Inducible T-Cell Kinase (ITK)-Mediated Chemoresistance By Ibrutinib in T-Cell Lymphoproliferative Disorders." Blood 126, no. 23 (December 3, 2015): 1467. http://dx.doi.org/10.1182/blood.v126.23.1467.1467.
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Abstract Background: Most (≈ 95%) T-cell lymphomas (TCL) express an intact T-cell receptor (TCR), suggesting that malignant T cells, like their B-cell counterparts, may benefit from antigen-receptor signaling. TCR engagement culminates in the activation of pathways required for T-cell proliferation and survival. The Tec family kinase and BTK homologue ITK is required for optimal TCR-dependent signaling. Therefore, we sought to understand whether TCR activation promotes chemotherapy resistance in TCL, and whether this may be overcome upon inhibition of ITK. Methods: TCL cell lines, mouse models and primary patient specimens were utilized. TCR signaling was engaged by anti-CD3/CD28 beads. ITK and GATA3 were inhibited by lentiviral-mediated shRNA knockdown and by ibrutinib, an ITK inhibitor. The chemoresistance of TCL cells was investigated in vitro and in vivo. Results: We have previously shown by gene expression profiling, proliferation, cytokine release, and signaling pathway analysis that TCR signaling remains intact in TCL [Blood, 2014, 124(21), 2959]. To further investigate the effect of TCR on chemoresistance, T8ML1 (a PTCL, NOS cell line) and primary cells from TCL patients (n=4) were treated with either vincristine or romidepsin in vitro. For T8ML1, the viability of cells treated with either vincristine or romidepsin increased by 2.9+/-0.14 fold or 1.4 +/- 0.035 fold respectively (p<0.01) upon TCR engagement. The enhanced viability of T8ML1 by TCR engagement under either vincristine or romidepsin treatment was abolished by shRNA-mediated ITK knockdown and significantly inhibited by ibrutinib (p<0.01). Similarly for primary TCL patient cells, the viability of cells treated with romidepsin increased by 2.4 +/- 0.35 fold upon TCR engagement, which was also significantly inhibited by ibrutinib treatment (p<0.01). To study the mechanism of TCR signaling in TCL chemoresistance, downstream targets of TCR signaling (NFκB, GATA3) were examined. Upon TCR engagement, NFκB activity increased by 1.7 +/- 0.22 fold in T8ML1 and 1.8 +/- 0.36 fold in primary cells from TCL patients (p<0.01) as shown by DNA-binding and nuclear localization. The activation of NFκB in T8ML1 and primary TCL patient cells was significantly inhibited by ibrutinib (p<0.01). We and others have previously shown that GATA3 identifies a distinct subset of PTCL, NOS that is characterized by inferior progression-free survival following anthracycline-based chemotherapy. [Blood, 2014, 123 (19), 3007-3015; Blood, 2014, 123(19), 2915-2923]. Furthermore, GATA-3 regulates the homeostatic survival of normal T cells following TCR engagement. In addition to NFκB, GATA3 protein increased by 3.0 +/- 0.45 fold in T8ML1 (p<0.01) and by 3.6 +/- 3.0 fold in primary TCL patient cells (p<0.03) upon TCR engagement, which was also inhibited by ibrutinib treatment. Furthermore, in T8ML1 cells, GATA3 upregulation by TCR engagement was abolished by shRNA-mediated ITK knockdown. To study the effect of GATA3 on chemoresistance, GATA3 was knocked down by lentiviral-mediated shRNAs in TCL cell lines (T8ML1, H9 and MyLa). The viability of TCL lines following GATA3 knockdown decreases by 2-4 fold (p<0.01) following treatment with either vincristine, romidepsin or 4-hydroxycyclophosphamide. In comparison to tumor xenografts generated fromTCL lines transduced with a non-targeting shRNA, GATA3 deficient tumor xenografts were significantly more sensitive to vincristine alone or combined vincristine/cyclophosphamide (p<0.01). Conclusions: TCR engagement promotes resistance to chemotherapy in T-cell lymphomas in an ITK- and GATA-3-dependent manner. Furthermore, chemotherapy resistance following TCR engagement is significantly impaired by ibrutinib. Therefore, ibrutinib may warrant further investigation in the T-cell lymphomas. Disclosures Off Label Use: We used ibrutinib to inhibit T-cell receptor signaling and discussed its clinical implication in T-cell lymphomas..
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Doré, Louis C., Timothy M. Chlon, Christopher D. Brown, Kevin P. White, and John D. Crispino. "Chromatin occupancy analysis reveals genome-wide GATA factor switching during hematopoiesis." Blood 119, no. 16 (April 19, 2012): 3724–33. http://dx.doi.org/10.1182/blood-2011-09-380634.
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Abstract There are many examples of transcription factor families whose members control gene expression profiles of diverse cell types. However, the mechanism by which closely related factors occupy distinct regulatory elements and impart lineage specificity is largely undefined. Here we demonstrate on a genome wide scale that the hematopoietic GATA factors GATA-1 and GATA-2 bind overlapping sets of genes, often at distinct sites, as a means to differentially regulate target gene expression and to regulate the balance between proliferation and differentiation. We also reveal that the GATA switch, which entails a chromatin occupancy exchange between GATA2 and GATA1 in the course of differentiation, operates on more than one-third of GATA1 bound genes. The switch is equally likely to lead to transcriptional activation or repression; and in general, GATA1 and GATA2 act oppositely on switch target genes. In addition, we show that genomic regions co-occupied by GATA2 and the ETS factor ETS1 are strongly enriched for regions marked by H3K4me3 and occupied by Pol II. Finally, by comparing GATA1 occupancy in erythroid cells and megakaryocytes, we find that the presence of ETS factor motifs is a major discriminator of megakaryocyte versus red cell specification.
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Ogasawara, Takashi, Masahiko Hatano, Hisae Satake, Jun Ikari, Toshibumi Taniguchi, Nobuhide Tsuruoka, Haruko Watanabe-Takano, et al. "Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells." Proceedings of the National Academy of Sciences 114, no. 5 (January 17, 2017): E741—E750. http://dx.doi.org/10.1073/pnas.1613528114.
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Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularlyInterleukin4(Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, includingIl4loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6’s association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.
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Sakata-Yanagimoto, Mamiko, Fumio Nakahara, Etsuko Yamaguchi-Nakagami, Keiki Kumano, Toshiki Saito, Mineo Kurokawa, Seishi Ogawa, and Shigeru Chiba. "Balance of Transcription Factors Downstream of Notch Signaling Determines the Fate of Myeloid Progenitors toward Differentiation to Mast Cells or Immortalization without Differentiation." Blood 108, no. 11 (November 16, 2006): 676. http://dx.doi.org/10.1182/blood.v108.11.676.676.
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Abstract Notch signaling represents one of the fundamental communication channels in various types of cells. While Notch activation has been shown to inhibit myeloid differentiation in a subset of hematopoietic progenitors, the role of Notch signaling in mast cell differentiation is not clear. When common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) purified from mouse bone marrow cells were stimulated with Delta1-Fc, a soluble form of Notch ligand, in the presence of stem cell factor, IL-3, IL-6, and thrombopoietin, granulocyte and macrophage differentiation, which is observed at day 7 of culture in the absence of Delta1-Fc, was markedly inhibited. Instead, Lin-c-Kit+FcεR+ mast cells dominated in the culture. Delta1-Fc did not increase mast cell generation from either CMPs or GMPs of the bone marrow of pI:pC-treated Mx-Cre x Notch2 flox/flox (N2-MxcKO) mice, in contrast to littermate Notch2 flox/flox mice treated with pI:pC, which suggests that Notch2 is responsible for the Delta1-Fc-augmented mast cell generation from CMPs and GMPs in culture. Retroviral transfer of constitutive active form of Notch2 (aN2) into CMPs and GMPs resulted in the complete loss of granulocyte-macrophage colony-forming cells and the emergence of basophilic granules-containing blast like cells, indicating the cell fate instruction. Real-time PCR analysis revealed that Delta1-Fc stimulation and aN2 introduction up-regulated the expression of Hes1, a transcriptional suppressor that is known to be a direct target of Notch activation in several cell types, within 12 h. Moreover, among GATA genes, Delta1-Fc stimulation and aN2 introduction resulted in increase of GATA3 mRNA, while expression levels of GATA1 and GATA2, which have been suggested to play a role in regulating mast cell differentiation, were unchanged. Next, we retrovirally expressed Hes1 and/or a GATA gene into CMPs and GMPs to see if the same effects were observed. Mast cells were increased only when both genes were expressed. On the other hand, when Hes1 alone was transduced, we observed rapid growth and immortalization of these cells without differentiation. C/EBPa, which is known to be suppressed in mast cell differentiation and upregulated in myeloid cell differentiation, was down-regulated within 48 h from the initiation of Hes1 retroviral transduction, suggesting that C/EBPa is a downstream target of Hes1 in this myeloid cell fate determination. Theses results indicate that, at the downstream of Notch activation, there are a C/EBPa down-regulation pathway that is Hes1-dependent and a GATA3 up-regulation pathway. Balanced regulation of these pathways should play a physiological role in myeloid and mast cell differentiation, while imbalance between these two pathways might provide a new model of myeloid transformation.
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Watkins, Nicholas A., Marloes R. Tijssen, Arief Gusnanto, Bernard de Bono, Subhajyoti De, Diego Miranda-Saavedra, Will Angenent, et al. "The HaemAtlas: Characterising Gene Expression in Differentiated Human Blood Cells." Blood 112, no. 11 (November 16, 2008): 2453. http://dx.doi.org/10.1182/blood.v112.11.2453.2453.
Full textAbstract:
Abstract Haematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell surface receptors. In order to further understand haematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B-cells, cytotoxic and helper T-cells, Natural Killer cells, granulocytes and monocytes using whole genome microarrays. A bioinformatics analysis of this data was performed focusing on transcription factors, immunoglobulin superfamily members and lineage specific transcripts. We observed that the numbers of lineage specific genes varies by two orders of magnitude, ranging from five for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel co-expression patterns for key transcription factors involved in haematopoiesis (eg. GATA3–GFI1 and GATA2–KLF1). This study represents the most comprehensive analysis of gene expression in haematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which is freely accessible, will be invaluable for future studies on haematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
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Watkins, Nicholas A., Arief Gusnanto, Bernard de Bono, Subhajyoti De, Diego Miranda-Saavedra, Debbie L. Hardie, Will G. J. Angenent, et al. "A HaemAtlas: characterizing gene expression in differentiated human blood cells." Blood 113, no. 19 (May 7, 2009): e1-e9. http://dx.doi.org/10.1182/blood-2008-06-162958.
Full textAbstract:
Abstract Hematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell-surface receptors. To further understand hematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B cells, cytotoxic and helper T cells, natural killer cells, granulocytes, and monocytes using whole genome microarrays. A bioinformatics analysis of these data was performed focusing on transcription factors, immunoglobulin superfamily members, and lineage-specific transcripts. We observed that the numbers of lineage-specific genes varies by 2 orders of magnitude, ranging from 5 for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel coexpression patterns for key transcription factors involved in hematopoiesis (eg, GATA3-GFI1 and GATA2-KLF1). This study represents the most comprehensive analysis of gene expression in hematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which are freely accessible, will be invaluable for future studies on hematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
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Jin, Yue, Yidi Guo, Dongxue Liang, Yue Li, Zhe Li, and Xin Hu. "LSD1 Plays an Important Role in GATA Switch during Erythroid Differentiation." Blood 122, no. 21 (November 15, 2013): 4846. http://dx.doi.org/10.1182/blood.v122.21.4846.4846.
Full textAbstract:
Abstract GATA factors play important role in hematopoiesis. In particular, GATA2 is critical for maintenance of hematopoietic stem and progenitor cells (HS/PCs) and GATA1 is required for erythropoiesis. GATA1 and GATA2 are expressed in reciprocal patterns during erythroid differentiation. It was shown that GATA1 occupied the -2.8Kb regulatory element and mediated repression of the GATA2 promoter in terminally differentiating erythroid cells. However, the detailed molecular mechanisms that control the enhancer/promoter activities of the GATA2 gene remain to be elucidated. In this report, we found that LSD1 and TAL1 co-localize at GATA2 1S promoter through ChIP and double-ChIP assays in murine erythroleukemia (MEL) cells. To further test whether LSD1 and its mediated H3K4 demethylation is important for repression of the GATA2 gene during erythroid differentiation, we silenced LSD1 expression in both MEL cells and mouse ES cells using retrovirus mediated shRNA knockdown and induced them to differentiate into erythroid cells with DMSO and EPO, respectively. GATA2 expression was elevated while the level of GATA1 was repressed by RT-qPCR. Furthermore, consistent with the GATA witch hypothesis, ChIP analysis revealed that the levels of H3K4me2 were increased at the GATA2 1S promoter. In addition, knock-down of LSD1 in MEL cells results in inhibition of erythroid cell differenciation and attenuation of MEL cell proliferation and survival. Thus, our data reveal that LSD1 involved in control of terminal erythroid differentiation by regulating GATA switch. The LSD1 histone demethylase complex may be recruited to the GATA2 1S promoter by interacting with TAL1. The H3K4 demethylation activity of LSD1 leads to downregulation of the active H3K4m2 mark at the GATA2 promoter that alters chromatin structure and represses transcription of the GATA2 genes. Disclosures: No relevant conflicts of interest to declare.
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Medeiros, Priscila, Weber Laurentino da Silva, Bruna Beatriz de Oliveira Gimenez, Keren Bastos Vallezi, Milton Ozório Moraes, Vânia Niéto Brito de Souza, and Ana Carla Pereira Latini. "The GATA3 gene is involved in leprosy susceptibility in Brazilian patients." Infection, Genetics and Evolution 39 (April 2016): 194–200. http://dx.doi.org/10.1016/j.meegid.2016.01.015.
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Airik, Rannar, Martin Kärner, Alar Karis, and Jüri Kärner. "Gene expression analysis of Gata3−/− mice by using cDNA microarray technology." Life Sciences 76, no. 22 (April 2005): 2559–68. http://dx.doi.org/10.1016/j.lfs.2004.10.054.
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