GATA-binding Factor Research Articles

Genome-Wide Analysis of GATA Transcription Factor Family in Quinoa (Chenopodium quinoa): Identification, Characterization, and Expression Profiles

GATA-binding factor (GATA) proteins are the transcription factor (TF) family that are commonly involved in plant growth and development. The GATA TF family has been successfully identified and characterized for various higher plant species, but there is little research on the GATA TF family in quinoa (Chenopodium quinoa). In this present study, a total of 32 CqGATA genes were identified and analyzed in the quinoa genome. While the general features of the CqGATA TFs in quinoa were slightly variable, the majority of genes encoding the CqGATA TFs contained two and three exons. Our phylogenetic analysis demonstrated that the CqGATA TFs could be classified into four different groups. Gene expression analysis indicated that the expression profiles of the CqGATA genes varied in different tissues. Overall, our study could provide a reference for further functional characterization of the CqGATA genes in quinoa.

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration

BackgroundLung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC. MethodsTo identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis. ResultsPLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6. ConclusionIn this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.

Identification of common genes of rhinovirus single/double‑stranded RNA‑induced asthma deterioration by bioinformatics analysis.

Rhinovirus (RV) is the most common respiratory virus affecting humans. The majority of asthma deteriorations are triggered by RV infections. However, whether the effects of RV single- and double-stranded RNA on asthma deterioration have common target genes needs to be further studied. In the present study, two datasets (GSE51392 and GSE30326) were used to screen for common differentially expressed genes (cDEGs). The molecular function, signaling pathways, interaction networks, hub genes, key modules and regulatory molecules of cDEGs were systematically analyzed using online tools such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, STRING and NetworkAnalyst. Finally, the hub genes STAT1 and IFIH1 were verified in clinical samples using reverse transcription-quantitative PCR (RT-qPCR). A total of 85 cDEGs were identified. Function analysis revealed that cDEGs served an important role in the innate immune response to viruses and its regulation. Signal transducer and activator of transcription 1 (STAT1), interferon induced with helicase C domain 1 (IFIH1), interferon regulatory factor 7 (IRF7), DExD/H box helicase 58 (DDX58) and interferon-stimulating gene 15 (ISG15) were detected to be hub genes based on the protein-protein interactions and six topological algorithms. A key module involved in influenza A, the Toll-like receptor signaling pathway, was identified using Cytoscape software. The hub genes were regulated by GATA-binding factor 2 and microRNA-146a-5p. In addition, RT-qPCR indicated that the expression levels of the hub genes STAT1 and IFIH1 were low during asthma deterioration compared with post-treatment recovery samples. The present study enhanced the understanding of the mechanism of RV-induced asthma deterioration.

Transcription Factor TAL1 in Erythropoiesis.

Lineage-specific transcription factors (TFs) regulate differentiation of hematopoietic stem cells (HSCs). They are decisive for the establishment and maintenance of lineage-specific gene expression programs during hematopoiesis. For this they create a regulatory network between TFs, epigenetic cofactors, and microRNAs. They activate cell-type specific genes and repress competing gene expression programs. Disturbance of this process leads to impaired lineage fidelity and diseases of the blood system. The TF T-cell acute leukemia 1 (TAL1) is central for erythroid differentiation and contributes to the formation of distinct gene regulatory complexes in progenitor cells and erythroid cells. A TAL1/E47 heterodimer binds to DNA with the TFs GATA-binding factor 1 and 2 (GATA1/2), the cofactors LIM domain only 1 and 2 (LMO1/2), and LIM domain-binding protein 1 (LDB1) to form a core TAL1 complex. Furthermore, cell-type-dependent interactions of TAL1 with other TFs such as with runt-related transcription factor 1 (RUNX1) and Kruppel-like factor 1 (KLF1) are established. Moreover, TAL1 activity is regulated by the formation of TAL1 isoforms, posttranslational modifications (PTMs), and microRNAs. Here, we describe the function of TAL1 in normal hematopoiesis with a focus on erythropoiesis.

Sibjotang Protects against Cardiac Hypertrophy In Vitro and In Vivo.

Cardiac hypertrophy is developed by various diseases such as myocardial infarction, valve diseases, hypertension, and aortic stenosis. Sibjotang (, Shizaotang, SJT), a classic formula in Korean traditional medicine, has been shown to modulate the equilibrium of body fluids and blood pressure. This research study sought to explore the impact and underlying process of Sibjotang on cardiotoxicity induced by DOX in H9c2 cells. In vitro, H9c2 cells were induced by DOX (1 μM) in the presence or absence of SJT (1-5 μg/mL) and incubated for 24 h. In vivo, SJT was administrated to isoproterenol (ISO)-induced cardiac hypertrophy mice (n = 8) at 100 mg/kg/day concentrations. Immunofluorescence staining revealed that SJT mitigated the enlargement of H9c2 cells caused by DOX in a dose-dependent way. Using SJT as a pretreatment notably suppressed the rise in cardiac hypertrophic marker levels induced by DOX. SJT inhibited the DOX-induced ERK1/2 and p38 MAPK signaling pathways. In addition, SJT significantly decreased the expression of the hypertrophy-associated transcription factor GATA binding factor 4 (GATA 4) induced by DOX. SJT also decreased hypertrophy-associated calcineurin and NFAT protein levels. Pretreatment with SJT significantly attenuated DOX-induced apoptosis-associated proteins such as Bax, caspase-3, and caspase-9 without affecting cell viability. In addition, the results of the in vivo study indicated that SJT significantly reduced the left ventricle/body weight ratio level. Administration of SJT reduced the expression of hypertrophy markers, such as ANP and BNP. These results suggest that SJT attenuates cardiac hypertrophy and heart failure induced by DOX or ISO through the inhibition of the calcineurin/NFAT/GATA4 pathway. Therefore, SJT may be a potential treatment for the prevention and treatment of cardiac hypertrophy that leads to heart failure.

Bimodular architecture of bacterial effector SAP05 that drives ubiquitin-independent targeted protein degradation.

In eukaryotes, targeted protein degradation (TPD) typically depends on a series of interactions among ubiquitin ligases that transfer ubiquitin molecules to substrates leading to degradation by the 26S proteasome. We previously identified that the bacterial effector protein SAP05 mediates ubiquitin-independent TPD. SAP05 forms a ternary complex via interactions with the von Willebrand Factor Type A (vWA) domain of the proteasomal ubiquitin receptor Rpn10 and the zinc-finger (ZnF) domains of the SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) and GATA BINDING FACTOR (GATA) transcription factors (TFs). This leads to direct TPD of the TFs by the 26S proteasome. Here, we report the crystal structures of the SAP05-Rpn10vWA complex at 2.17 Å resolution and of the SAP05-SPL5ZnF complex at 2.20 Å resolution. Structural analyses revealed that SAP05 displays a remarkable bimodular architecture with two distinct nonoverlapping surfaces, a "loop surface" with three protruding loops that form electrostatic interactions with ZnF, and a "sheet surface" featuring two β-sheets, loops, and α-helices that establish polar interactions with vWA. SAP05 binding to ZnF TFs involves single amino acids responsible for multiple contacts, while SAP05 binding to vWA is more stable due to the necessity of multiple mutations to break the interaction. In addition, positioning of the SAP05 complex on the 26S proteasome points to a mechanism of protein degradation. Collectively, our findings demonstrate how a small bacterial bimodular protein can bypass the canonical ubiquitin-proteasome proteolysis pathway, enabling ubiquitin-independent TPD in eukaryotic cells. This knowledge holds significant potential for the creation of TPD technologies.

Blocking the interaction between circTNRC18 and LIN28A promotes trophoblast epithelial–mesenchymal transformation and alleviates preeclampsia

Defects in migration and invasion caused by dysregulation of trophoblastic epithelial–mesenchymal transformation (EMT) play a vital role in preeclampsia (PE). We have previously shown that circTNRC18 inhibits the migration and EMT of trophoblasts; however, its role in PE remains unknown. Herein, we demonstrate that circTNRC18 interacts with an RNA-binding protein, lin-28 homolog A (LIN28A), and this interaction is enhanced in PE placental tissue. LIN28A overexpression suppresses circTNRC18-mediated inhibition of trophoblast migration, invasion, and EMT, whereas LIN28A knockdown promotes them. The intracellular distribution of LIN28A is regulated by circTNRC18, where it promotes the expression of insulin-like growth factor II by stabilizing its mRNA. circTNRC18 also promotes complex formation between GATA-binding factor 1 (GATA1) and sine oculis homeobox 1 (SIX1) by inhibiting LIN28A–GATA1 interaction. GATA1–SIX1 promotes transcription of grainyhead-like protein 2 homolog and circTNRC18-mediated regulation of cell migration and invasion. Moreover, blocking circTNRC18–LIN28A interaction with antisense nucleotides alleviates PE in a mouse model of reduced uterine perfusion pressure. Thus, targeting the circTNRC18–LIN28A regulatory axis may be a novel PE treatment method.

HEXIM1 is an essential transcription regulator during human erythropoiesis

AbstractRegulation of RNA polymerase II (RNAPII) activity is an essential process that governs gene expression; however, its contribution to the fundamental process of erythropoiesis remains unclear. hexamethylene bis-acetamide inducible 1 (HEXIM1) regulates RNAPII activity by controlling the location and activity of positive transcription factor β. We identified a key role for HEXIM1 in controlling erythroid gene expression and function, with overexpression of HEXIM1 promoting erythroid proliferation and fetal globin expression. HEXIM1 regulated erythroid proliferation by enforcing RNAPII pausing at cell cycle check point genes and increasing RNAPII occupancy at genes that promote cycle progression. Genome-wide profiling of HEXIM1 revealed that it was increased at both repressed and activated genes. Surprisingly, there were also genome-wide changes in the distribution of GATA-binding factor 1 (GATA1) and RNAPII. The most dramatic changes occurred at the β-globin loci, where there was loss of RNAPII and GATA1 at β-globin and gain of these factors at γ-globin. This resulted in increased expression of fetal globin, and BGLT3, a long noncoding RNA in the β-globin locus that regulates fetal globin expression. GATA1 was a key determinant of the ability of HEXIM1 to repress or activate gene expression. Genes that gained both HEXIM1 and GATA1 had increased RNAPII and increased gene expression, whereas genes that gained HEXIM1 but lost GATA1 had an increase in RNAPII pausing and decreased expression. Together, our findings reveal a central role for universal transcription machinery in regulating key aspects of erythropoiesis, including cell cycle progression and fetal gene expression, which could be exploited for therapeutic benefit.

GATA4 rs61277615, rs73203482, and rs35813172 in Newborns with Transposition of the Great Arteries.

Congenital heart disease is the most common malformative pathology in newborns, with a worldwide incidence at 0.4-5%. We investigated the possible relationship between variations in nucleotide sequences and specific cardiac malformations in the GATA-binding factor 4 (GATA4) exon 1 region by using Sanger sequencing. Forty-four newborns from a third-level neonatal intensive care unit who were diagnosed with nonsyndromic, ductal-dependent congenital heart disease (i.e., transposition of the great arteries or ductal-dependent coarctation of the aorta) were enrolled. Their DNA was extracted using commercial methods and tested using the multiplex ligation-dependent probe amplification (MLPA) technique. The Sanger sequencing for GATA4 exon 1 in the newborns' DNA identified rs61277615, rs73203482, and rs35813172 variants not reported in the ClinVar archive of human variations in newborns previously diagnosed with transposition of the great arteries (n=5) and coarctation of the aorta (n=1). The identification of these novel variants in newborns with transposition of the great arteries or ductal-dependent coarctation of the aorta may be the first step in determining the variants' contribution to the occurrence of congenital heart disease. However, these results may be inconclusive, since the observed variants within GATA4 gene were not previously reported.

Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Pannier is a key regulator of embryogenesis, pupal development and female reproduction in the insect pest Bactrocera dorsalis.

Most arthropods are famous for their large reproductive capacity, with the ovary playing a vital role in the process. The study of the regulatory mechanisms of ovarian development may have the potential for a reproduction-based pest management strategy. GATA-binding transcription factors (GATAs) as important regulatory factors mediate many physiological processes, including development, immunity, insecticide resistance and reproduction. The Pannier (pnr), a member of GATA family, was confirmed to be involved in ovarian development of Bactrocera dorsalis in our previous study. However, the direct evidence of pnr regulating the fly ovarian development is still lacking. We used CRISPR/Cas9 to create Bdpnr loss-of-function mutations. Homozygous Bdpnr-/- mutants were nonviable, with most individuals dying during embryogenesis, some surviving to the larval stages, and the remaining few dying during pupation. In contrast, heterozygous individuals reached the adult stage, but ovarian development was disrupted, with concomitant decreases in egg laying and hatching rates. We also found that two genes encoding vitellogenin proteins (BdVg1 and BdVg2) and the vitellogenin receptor (BdVgR) were significantly down-regulated in heterozygous mutants compared to wild-type controls. These results indicate that Bdpnr is required for embryonic and post-embryonic development, including the formation of ovaries. Bdpnr could therefore be considered as a molecular target for tephritid fly pest control. © 2022 Society of Chemical Industry.

BMP6 regulates AMH expression via SMAD1/5/8 in goat ovarian granulosa cells

Anti-Müllerian hormone (AMH) is produced by ovarian granulosa cells (GCs)and plays a major role in inhibiting the recruitment of primordial follicles and reducing the sensitivity of growing follicles to follicle-stimulating hormone (FSH). Bone morphogenetic protein 6 (BMP6) has similar spatiotemporal expression to AMH during follicular development, suggesting that BMP6 may regulate AMH expression. However, the specific mechanism by which BMP6 regulates AMH expression remains unclear. The objectives of this study were to examine the molecular pathway by which BMP6 regulates AMH expression. The results showed that BMP6 promoted the secretion and expression of AMH in goat ovarian GCs. Mechanistically, BMP6 upregulated the expression of sex-determining region Y-box 9 (SOX9) and GATA-binding factor 4 (GATA4), which was associated with the transcriptional initiation of AMH. AMH expression was significantly decreased by GATA4 knockdown. Moreover, BMP6 treatment promoted the phosphorylation of SMAD1/5/8, whereas inhibiting the SMAD1/5/8 signaling pathway significantly abolished BMP6-induced upregulation of AMH and GATA4 expression. Interestingly, the activation of SMAD1/5/8 alone did not affect the expression of AMH or GATA4. The results suggested that BMP6 upregulated GATA4 through the SMAD1/5/8 signaling pathway, which in turn promoted AMH expression.

An artificial LAMA2-GelMA hydrogel microenvironment for the development of pancreatic endocrine progenitors

The biomimetic pancreatic microenvironment improves the differentiation efficiency and function of human embryonic stem cell-derived β-cells (SC-β cells). Thus, a laminin subunit alpha 2-gelatin methacrylate (LAMA2-GelMA) hybrid hydrogel as a bionics carrier for the formation and maturation of endocrine lineage was developed in our research, based on pancreas proteomics analysis of postnatal mice. Pancreatic endocrine cells cultured on the hybrid hydrogel in vitro, which was composed of 0.5 μg/mL LAMA2 protein and 4% GelMA, the expression of transcription factors (TFs), including NKX6.1, NKX6.2, and NEUROD1 were upregulated. Single-cell transcriptomics was performed after LAMA2 knockdown during the early differentiation of pancreatic progenitor (PP) cells, a marked decrease in the forkhead box protein A2 (FOXA2+)/GATA-binding factor 6 (GATA6+) cluster was detected. Also, we clarified that as a receptor of LAMA2, integrin subunit alpha 7 (ITGA7) participated in Integrin-AKT signaling transduction and influenced the protein levels of FOXA2 and PDX1. In vivo experiments showed that, PP cells encapsulated in the LAMA2-GelMA hydrogel exhibited higher serum C-peptide levels compared to the GelMA and Matrigel groups in nude mice and reversed hyperglycemia more quickly in STZ-induced diabetic nude mice. Taken together, our findings highlighted the feasibility of constructing a pancreas-specific microenvironment based on proteomics and tissue engineering for the treatment of diabetes.

MiR-309a is a regulator of ovarian development in the oriental fruit fly Bactrocera dorsalis.

Fecundity is arguably one of the most important life history traits, as it is closely tied to fitness. Most arthropods are recognized for their extreme reproductive capacity. For example, a single female of the oriental fruit fly Bactrocera dorsalis, a highly invasive species that is one of the most destructive agricultural pests worldwide, can lay more than 3000 eggs during its life span. The ovary is crucial for insect reproduction and its development requires further investigation at the molecular level. We report here that miR-309a is a regulator of ovarian development in B. dorsalis. Our bioinformatics and molecular studies have revealed that miR-309a binds the transcription factor pannier (GATA-binding factor A/pnr), and this activates yolk vitellogenin 2 (Vg 2) and vitellogenin receptor (VgR) advancing ovarian development. We further show that miR-309a is under the control of juvenile hormone (JH) and independent from 20-hydroxyecdysone. Thus, we identified a JH-controlled miR-309a/pnr axis that regulates Vg2 and VgR to control the ovarian development. This study has further enhanced our understanding of molecular mechanisms governing ovarian development and insect reproduction. It provides a background for identifying targets for controlling important Dipteran pests.

Interaction of epithelium and myofibroblasts through ERBB3‐PDGF growth pathways crosstalk drive the maturation of distal lung epithelium in late stage lung development

RationaleThe last stage of lung development is realized by coordinated growth of septae from the alveolar walls to subdivide the distal saccules into alveoli, resulting in the expansion of surface area for gas exchange. The process is accompanied by microvascular maturation and underlying matrix formation of the interstitial scaffold. Secondary septation is driven by the orchestration of the distal epithelium, endothelium, and fibroblasts through the spatial and temporal distribution of various growth pathways and their crosstalk.This study investigated the role of the receptor tyrosine kinases 3 (ERBB3) pathway in the fibroblast‐epithelial crosstalk during septation using both in vitro co‐cultures and ex vivo organoid model as well as transgenic mice.MethodsPrimary myofibroblasts were extracted from neonatal C57BL/6wildtype (WT) mice at postnatal day 7 (PND7) and co‐cultured with a murine epithelial cell line (MLE12) in transwell inserts for 24h before sample collection. Gene expression was analyzed by quantitative PCR. Neonatal lung organoids were generated from primary lung epithelial cells (CD45‐/CD31‐) from neonatal C57BL/6 WT mice (PND7) and cultured in matrigel together with primary myofibroblasts from neonatal WT mice (PND7) as well as age matched mice heterozygot for the Platelet‐derived growth factor receptors (PDGF‐Rα+/‐). After organoid formation, cultures were treated with Neuregulin (NRG), an activating ligand of the ERBB3 receptor. We measured organoid number and size and Erbb3 signaling was assessed by immunofluorescence and quantitative gene expression analyses.ResultsProximal culture with myofibroblasts upregulated the expression level of ERBB3 receptor in epithelial cells, as well as homeodomain‐only protein homeobox (HOPX), GATA‐binding factor 6 (GATA6), both of which are essential in the differentiation of distal epithelial cells and surfactant production during late stage lung development. In neonatal lung organoids, myofibroblasts with reduced PDGFRα expression led to reduction in organoid size and number. Treatment with the Erbb3 ligand NRG significantly increased both the expression and phosphorylation of Erbb3 in epithelial cells together with an upregulation of surfactant C (SPC) expression, and an increase in myofibroblasts PDGF‐R α expression.ConclusionActivated Erbb3 signaling results from the interaction with fibroblasts involving PDGF‐Rα signaling and drives distal epithelium maturation.

GATA6+ Peritoneal Resident Macrophage: The Immune Custodian in the Peritoneal Cavity.

Peritoneal resident macrophages (PRMs) have been a prominent topic in the research field of immunology due to their critical roles in immune surveillance in the peritoneal cavity. PRMs initially develop from embryonic progenitor cells and are replenished by bone marrow origin monocytes during inflammation and aging. Furthermore, PRMs have been shown to crosstalk with other cells in the peritoneal cavity to control the immune response during infection, injury, and tumorigenesis. With the advance in genetic studies, GATA-binding factor 6 (GATA6) has been identified as a lineage determining transcription factor of PRMs controlling the phenotypic and functional features of PRMs. Here, we review recent advances in the developmental origin, the phenotypic identity, and functions of PRMs, emphasizing the role of GATA6 in the pathobiology of PRMs in host defense, tissue repairing, and peritoneal tumorigenesis.

Tissue eosinophilia correlates with mice susceptibility, granuloma formation, and damage during Toxocara canis infection.

AbstractAn increase in peripheral blood eosinophils in helminth infections is expected, and these cells are known to promote immunity against these parasites. However, studies have suggested that in some specific helminths, eosinophils may promote the needs and longevity of these parasites, and their role in these infections remains undefined, including in Toxocara canis infection. Thus, this study aimed to investigate the role of eosinophils in the context of larval migration of T. canis and the immunopathological aspects of infection. For this, we used wild-type mice and mice genetically deficient for the transcription factor GATA-binding factor 1 (GATA1−/−), infected with 1000 eggs of T. canis. At 0, 3, 14 and 63 days post-infection, parasite load, tissue cytokine production, leucocyte profile, bronchoalveolar lavage cells and histopathological analyses were carried out. Collectively, our results demonstrate that the presence of eosinophils mediates susceptibility to T. canis, inducing leucocytosis and the formation of granulomas, increasing the pulmonary and cerebral parasite load, and reducing the number of neutrophils, which may be necessary to control the infection.

Multimerization of the GATA4 transcription factor regulates transcriptional activity and cardiomyocyte hypertrophic response.

The activation of the GATA-binding factor 4 (GATA4) transcription factor induces cardiac hypertrophy and heart failure. The multimerization of transcription factors often plays an important role in the regulation of transcriptional activity. Here, we report that the GATA4 transcription factor forms a homomultimer and that residues 308-326 of GATA4 are necessary for its multimerization. The acetylation of GATA4 by the transcriptional co-activator p300 induces the multimerization of GATA4 and activates its DNA binding activity. In addition, we found that the suppression of GATA4 multimerization did not reduce its acetylation, but repressed GATA4/p300-induced gene transcription. Furthermore, the inhibition of GATA4 multimerization suppressed phenylephrine (PE)-induced hypertrophic response in cardiomyocytes. This study demonstrates that the multimerization of GATA4 during the p300-induced acetylation of GATA4 activates the transcription of hypertrophic response genes, which leads to cardiomyocyte hypertrophy. Therefore, the inhibition of GATA4 homomultimerization could serve as a potential therapeutic strategy for the development of novel drugs against heart failure.

Cytology, function and dynamics of stem and progenitor cells in decapod crustaceans.

Stem cells play key roles in development, tissue homeostasis, regeneration, ageing and diseases. Comprehensive reviews on stem cells are available for the determinately growing mammals and insects and some lower invertebrates like hydra but are rare for larger, indeterminately growing invertebrates that can live for many decades. This paper reviews the cytology, function and dynamics of stem and progenitor cells in the decapod crustaceans, a species-rich and ecologically and economically important animal group that includes mainly indeterminate growers but also some determinate growers. Further advantages of decapods for stem cell research are almost 1000-fold differences in body size and longevity, the regeneration of damaged appendages and the virtual absence of age-related diseases and tumours in the indeterminately growing species. The available data demonstrate that the Decapoda possess a remarkable variety of structurally and functionally different stem cells in embryos and larvae, and in the epidermis, musculature, haematopoietic tissue, heart, brain, hepatopancreas, olfactory sense organs and gonads of adults. Some of these seem to be rather continuously active over a lifetime but others are cyclically activated and silenced in periods of days, weeks and years, depending on the specific organ and function. Stem cell proliferation is triggered by signals related to development, moulting, feeding, reproduction, injury, infection, environmental enrichment and social status. Some regulatory pathways have already been identified, including the evolutionarily conserved GATA-binding and runt-domain transcription factors, the widespread neurotransmitter serotonin, the arthropod-specific hormone 20-hydroxyecdysone and the novel astakine growth factors. Knowledge of stem cells in decapods primarily refines our picture on the development, growth and maintenance of tissues and organs in this animal group. Cultured decapod stem cells have good potential for toxicity testing and virus research with practical relevance for aquaculture. Knowledge of stem cells in decapods also broadens our understanding of the evolution of stem cells and regeneration in the animal kingdom. The stem cells of long-lived, indeterminately growing decapods may hold the key to understanding how stem and progenitor cells function into old age without adverse side effects, possibly evoking new ideas for the development of anti-ageing and anti-cancer treatments in humans.

Association Between Estrogen Receptors and GATA3 in Bladder Cancer: A Systematic Review and Meta-Analysis of Their Clinicopathological Significance.

BackgroundEstrogen receptors alpha (ERα) and beta (ERβ) and the cooperating protein GATA-binding factor 3 (GATA3) have been implicated in bladder carcinogenesis and tumour progression. GATA3 and ER have been functionally linked in the establishment of luminal fate in breast tissue, but to date their relationship in bladder cancer has not been established. This information will be useful to advance diagnostic and prognostic markers.AimTo determine the relationship between the expression of ERα, ERβ and GATA3 in bladder cancer, disclose their prognostic and diagnostic value and their association with clinicopathological characteristics.MethodsA comprehensive literature search in PubMed database was performed for all immunohistochemical studies of ERα, ERβ and/or GATA3 in bladder cancer patients. We selected eligible studies in accordance with the PRISMA guidelines and evaluated methodological quality and risk of bias based on quality criteria from the reporting recommendations for tumour MARKer (REMARK) prognostic studies. Risk of bias assessment was performed using Review Manager 5. R software was used for all statistical analysis, the packages used were meta and dmetar for the standard meta-analysis, and netmeta for the network meta-analysis.ResultsThirteen studies were eligible for ERα, 5 for ERβ and 58 for GATA3 meta-analysis. Low grade tumours showed significantly lower ERα expression. GATA3 was widely expressed in bladder tumours, especially urothelial carcinomas, with higher expression of GATA3 in low grade and low stage tumours. Data was insufficient to determine the prognostic value of either ERα or ERβ, but GATA3-positivity was associated with higher recurrence free survival. A negative correlation between ERα or ERβ positivity and GATA3 expression was disclosed. Additionally, several sources of heterogeneity were identified, which can be used to improve future studies.ConclusionThe clinicopathological value of ERα and ERβ was inconclusive due to low availability of studies using validated antibodies. Still, this meta-analysis supports GATA3 as good prognostic marker. On the contrary, ERα-positivity was associated to higher grade tumours; while ERα and ERβ were inversely correlated with GATA3 expression. Considering that it has previously been shown that bladder cancer cell lines have functional ERs, this suggests that ERα could be activated in less differentiated cells and independently of GATA3. Therefore, a comprehensive analysis of ERα and ERβ expression in BlaCa supported by complete patient clinical history is required for the identification of BlaCa subtypes and subgroups of patients expressing ERα, to investigate if they could benefit from treatment with hormonal therapy.Systematic Review RegistrationProspero, CRD42021226836.