The GATA family of transcriptional regulators is broadly conserved between plant and animal kingdoms. Here, we report that some of the GATA genes are suppressed in Arabidopsis during fungal and bacterial infections. However, strikingly, GATA21 and GATA22 encode positive regulators of defense against necrotrophic fungal pathogens while acting antagonistically against hemibiotrophic bacterial pathogens. Following infection by Verticillium dahliae, the gata21 and gata22 mutants exhibit defective growth in bolt length and in total silique number. These results suggest that GATA21 and GATA22 regulate growth and reproduction in Arabidopsis both during normal growth and in response to infection by pathogens. Because the GATA family is conserved, our findings have broad implications for the role of GATA transcription regulators in integrating signals from biotic interactions with those for growth and development. [Formula: see text] Copyright © 2025 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH) secretion or action and results in hypocalcaemia, and can lead to hyperphosphataemia and hypercalciuria. Most cases of hypoparathyroidism occur as a complication of surgery, with the remainder due to causes including autoimmune disease, genetic causes, infiltrative diseases, mineral deposition or due to abnormalities in serum levels of magnesium. Hypoparathyroidism can cause multisystem disease, with long-term complications resulting from ectopic calcification as well as renal complications with nephrocalcinosis, nephrolithiasis and renal impairment in addition to respiratory, cardiac or neurological manifestations. Conventional therapy consists of oral calcium salts and active vitamin D but it has limitations, including fluctuations in serum levels of calcium and a high pill burden, and can increase the risk of long-term complications. By contrast, PTH replacement therapy can effectively achieve normal serum levels of calcium, and lower serum levels of phosphate. The long-acting PTH analogue, palopegteriparatide, has been shown to normalize urine levels of calcium. In addition, PTH replacement therapy reduces the pill burden. Palopegteriparatide is also associated with improved quality of life in comparison to conventional therapy. This Review summarizes current recommendations regarding the pathophysiology, evaluation and management of hypoparathyroidism and also references the 2022 international hypoparathyroidism guidelines. Palopegteriparatide has now been approved as PTH replacement therapy for hypoparathyroidism. Emerging therapies will also be presented in this Review.

Phase separation (PS) underlies gene control by transcription factors. However, little is known about whether and how DNA-binding domains (DBDs) regulate the PS for transcription factors to differentially regulate the transcriptome. The transcription factor GATA3, a master immune regulator, is frequently mutated in breast cancer. Here, we report that GATA3 undergoes DBD-modulated PS to mediate the formation of chromatin condensates. We show that the DBD regulates the GATA3 PS through its zinc finger 2 (ZnF2) domain, which provides positive charges for multivalent electrostatic interactions mainly via two arginine amino acids, R329 and R330. Compared with breast-cancer-associated GATA3 without ZnF2-defective mutations, breast cancer GATA3 with ZnF2-defective mutations causes aberrant ZnF2-modulated PS and condensate formation to remodel the differentially regulated transcriptome, resulting in a favorable prognosis for patients and reduced tumor growth in mice. Therefore, GATA3 demonstrates a principle of how a transcription factor differentially regulates the transcriptome via DBD-modulated PS.

Stemness-associated cell states are linked to chemotherapy resistance in acute myeloid leukemia (AML). We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intrapatient and interpatient variability in GATA2 expression across samples from patients with AML. GATA2 expression varies by molecular subtype and has been linked to outcome. In a murine model, KMT2A-MLL3-driven AML originating from a stem cell or immature progenitor cell population has higher Gata2 expression and is more resistant to the standard AML chemotherapy agent doxorubicin. Deletion of Gata2 resulted in a more robust induction of p53 after exposure to doxorubicin. Chromatin immunoprecipitation sequencing, RNA sequencing, and functional studies revealed that GATA2 regulates the expression of RASSF4, a modulator of the p53 inhibitor MDM2 (mouse double minute 2). GATA2 and RASSF4 are anticorrelated in human cell lines and in bulk and single-cell expression data sets from patients with AML. Knockdown of Rassf4 in Gata2-low cells resulted in doxorubicin or nutlin-3 resistance. Conversely, overexpression of Rassf4 results in sensitization of cells expressing high levels of Gata2. Finally, doxorubicin and nutlin-3 are synergistic in Gata2-high murine AML and in samples from patients with AML. We discovered a previously unappreciated role for GATA2 in dampening p53-mediated apoptosis via transcriptional regulation of RASSF4, a modulator of MDM2. This role for GATA2 directly links the expression of a stemness-associated transcription factor to chemotherapy resistance.

Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Furthermore, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.

Identifying the genetic determinants of host defence against infectious pathogens is central to enhancing disease resilience and therapeutic efficacy in livestock. Here, we investigated immune response heritability to important infectious diseases affecting smallholder dairy cattle using variance component analysis. We also conducted genome-wide association studies (GWAS) to identify genetic variants that may help understand the underlying biology of these health traits. By assessing 668,911 single-nucleotide polymorphisms (SNPs) genotyped in 2,045 crossbred cattle sampled from six regions of Tanzania, we identified high levels of interregional admixture and European introgression, which may increase infectious disease susceptibility relative to indigenous breeds. Heritability estimates were low to moderate, ranging from 0.03 (SE ± 0.06) to 0.44 (SE ± 0.07), depending on the health trait. GWAS results revealed several loci associated with seropositivity to the viral diseases Rift Valley fever and bovine viral diarrhoea, the protozoan parasites Neospora caninum and Toxoplasma gondii, and the bacterial pathogens Brucella sp, Leptospira hardjo, and Coxiella burnetii. The identified quantitative trait loci mapped to genes involved in immune defence, tumour suppression, neurological processes, and cell exocytosis. We propose that our results provide a basis for future understanding of the cellular pathways contributing to general and taxon-specific infection responses, and for advancing selective breeding and therapeutic target design.

Tricho-rhino-phalangeal syndrome-1 (TRPS1), an atypical GATA transcription factor, plays a critical role in diverse physiological and pathological processes and holds potential as a biomarker for diseases and targeted tumor therapies. This study explores TRPS1 expression in ovarian clear cell carcinoma (OCCC), its correlation with patient prognosis, and its involvement in OCCC pathogenesis.

To investigate TRPS1 expression, we analyzed ovarian tissues from 50 OCCC patients and 25 normal tissues (from patients with uterine leiomyoma) via immunohistochemistry. Statistical methods, including Chi-square tests, Kaplan-Meier survival analysis, and Cox regression, were employed to evaluate the correlation between TRPS1 expression and clinicopathological parameters. In OCCC cell lines (TOV21G and ES-2), TRPS1 expression was quantified using qRT-PCR and Western blot. Functional studies were conducted by silencing TRPS1 in TOV21G cells with small interfering RNA and inducing overexpression in ES-2 cells using a plasmid. Cellular proliferation and migration were assessed through CCK-8, colony formation, and Transwell assays. Finally, Western blot analysis was performed to investigate the link between TRPS1 and EMT-related molecular pathways.

TRPS1 protein expression was significantly higher in OCCC tissues compared to normal tissues and was positively associated with lymph node metastasis and advanced clinical stage. High TRPS1 expression was linked to shorter overall and recurrence-free survival in OCCC patients. In vitro, TRPS1 knockdown suppressed cell proliferation, migration, and invasion, accompanied by reduced levels of invasion-promoting proteins (N-cadherin, MMP2, MMP9) and increased expression of the invasion-inhibiting protein E-cadherin. Conversely, TRPS1 overexpression promoted the expression of invasion-promoting proteins.

TRPS1 is overexpressed in OCCC and is associated with poor prognosis, serving as an independent predictor of patient outcomes. Its elevated expression enhances OCCC cell proliferation, migration, and invasion by regulating proteins involved in the epithelial-to-mesenchymal transition (EMT) pathway. These findings highlight TRPS1 as a critical player in OCCC pathogenesis and a potential biomarker and therapeutic target for disease management.

Early-stage generalised transcription factors in biological development are often evolutionarily conserved across species. Here, we find for the first time that similar factors functionally emerge in an alternative medium of development. Through comprehensively analysing a Neural Cellular Automata (NCA) model of morphogenesis, we find multiple properties of the hidden units that are functionally analogous to early factors in biological development. We test the generalisation abilities of our model through transfer learning of other morphologies and find that developmental strategies learnt by the model are reused to grow new body forms by conserving its early generalised factors. Our paper therefore provides evidence that nature did not become locked into one arbitrary method of developing multicellular organisms: the use of early generalised factors as fundamental control mechanisms and the resulting necessity for evolutionary conservation of those factors may be fundamental to development, regardless of the details of how development is implemented.

Several human transcription factors (TFs) have been reported to directly bind RNA through noncanonical RNA-binding domains; however, most of these TFs remain to be further validated as bona fide RNA-binding proteins (RBPs). Our systematic analysis of RBP discovery data sets reveals a varied set of candidate TF-RBPs that encompass most TF families. These candidate RBPs include members of the GATA family that are essential factors in embryonic development. Investigation of the RNA-binding features of GATA1, a major hematopoietic TF, reveals robust sequence independent binding to RNAs in vitro. Moreover, RNA binding by GATA1 is competitive with DNA binding, which occurs through a shared binding surface spanning the DNA-binding domain and arginine-rich motif (ARM)-like domain. We show that the ARM-like domain contributes substantially to high-affinity DNA binding and electrostatically to plastic RNA recognition, suggesting that the separable RNA-binding domain assigned to the ARM-domain in GATA1 is an oversimplification of a more complex recognition network. These biochemical data demonstrate a unified integration of DNA- and RNA-binding surfaces within GATA1, whereby the ARM-like domain provides an electrostatic surface for RNA binding but does not fully dominate GATA1-RNA interactions, which may also apply to other TF-RBPs. This competitive DNA/RNA binding activity using overlapping nucleic acid binding regions points to the possibility of RNA-mediated regulation of the GATA1 function during hematopoiesis. Our study highlights the multifunctionality of DNA-binding domains in RNA recognition and supports the need for robust characterization of predicted noncanonical RNA-binding domains such as ARM-like domains.

Glutathione S-transferases constitute a superfamily of enzymes involved mainly, but not exclusively, in the detoxification of xenobiotic compounds that are considered environmental pollutants. In this work, an updated analysis of putative cytosolic glutathione S-transferases (cGST) from ciliate protozoa is performed although this analysis is mainly focused on Tetrahymena thermophila. Among ciliates, the genus Tetrahymena has the highest number (58 on average) of cGST genes. As in mammals, the Mu class of cGST is present in all analyzed ciliates and is the majority class in Tetrahymena species. After an analysis of the occurrence of GST domains in T. thermophila, out of the 54 GSTs previously considered to be Mu class, six of them have been discarded as they do not have recognizable GST domains. In addition, there is one GST species-specific and another GST-EF1G (elongation factor 1 gamma). A structural analysis of T. thermophila GSTs has shown a wide variety of β-sheets/α-helix patterns, one of the most abundant being the canonical thioredoxin-folding pattern. Within the categories of bZIP and C4 zinc finger transcription factors, potential binding sites for c-Jun and c-Fos are abundant (32% as average), along with GATA-1 (71% average) in the T. thermophila GST gene promoters. The alignment of all MAPEG (Membrane Associated Proteins involved in Eicosanoid and Glutathione metabolism) GST protein sequences from Tetrahymena species shows that this family is divided into two well-defined clans. The phylogenetic analysis of T. thermophila GSTs has shown that a cluster of 19 Mu-class GST genes are phylogenetic predecessors of members from the omega, theta and zeta classes. This means that the current GST phylogenetic model needs to be modified. Sixteen T. thermophila GST genes, together with two clusters including three genes each with very high identity, have been selected for qRT-PCR analysis under stress from eleven different environmental stressors. This analysis has revealed that there are GST genes that respond selectively and/or differentially to each stressor, independently of the GST class to which it belongs. Most of them respond to the two more toxic metal(loid)s used (Cd or As).

Pediatric glioblastoma is a complex dynamical disease that is difficult to treat due to its multiple adaptive behaviors driven largely by phenotypic plasticity. Integrated data science and network theory pipelines offer novel approaches to studying glioblastoma cell fate dynamics, particularly phenotypic transitions over time. Here we used various single-cell trajectory inference algorithms to infer signaling dynamics regulating pediatric glioblastoma-immune cell networks. We identified GATA2, PTPRZ1, TPT1, MTRNR2L1/2, OLIG1/2, SOX11, FXYD6, SEZ6L, PDGFRA, EGFR, S100B, WNT, TNF α , and NF-kB as critical transition genes or signals regulating glioblastoma-immune network dynamics, revealing potential clinically relevant targets. Further, we reconstructed glioblastoma cell fate attractors and found complex bifurcation dynamics within glioblastoma phenotypic transitions, suggesting that a causal pattern may be driving glioblastoma evolution and cell fate decision-making. Together, our findings have implications for developing targeted therapies against glioblastoma, and the continued integration of quantitative approaches and artificial intelligence (AI) to understand pediatric glioblastoma tumor-immune interactions.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant genetic disease associated with mutations in the GATA3 gene, which encodes GATA3 that plays essential roles in vertebrate development. This study aimed to identify and report the pathogenic mutation in GATA3 in a Chinese family diagnosed with HDR syndrome and determine its functional impacts in vivo.

The clinical features of a 25-year-old male patient with HDR syndrome and his parents were collected. GATA3 gene exome sequencing and Sanger sequencing were performed on the proband and his family, respectively. Functional analyses of GATA3 were performed using bioinformatics tools and zebrafish assays to determine pathogenicity and phenotype spectrum.

A novel, heterozygous, missense mutation in exon 4 of the GATA3 gene, c.863 G > A, p.Cys288Tyr, in the proband and his mother who presented the complete HDR triad, was predicted to be deleterious by in silico tools. 3D structure modeling showed that the variant caused significant structural changes. In vivo studies using a zebrafish animal model revealed the deleterious impact of the variant on the gill buds, otoliths, and pronephros.

We identified a novel missense mutation, GATA3 p.Cys288Tyr, within a family with HDR syndrome and delineated it as a loss-of-function variant in vivo. This expands the spectrum of GATA3 mutations associated with HDR syndrome in the Chinese population and mimics HDR-related changes in vivo.

One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important roles in embryonic development and their inactivation may result in congenital heart defects (CHDs). In this study, we performed genotypic-phenotypic analyses in two families affected by right-sided CHD diagnosed by echocardiography imaging. Proband A presented with pulmonary valve stenosis, and proband B presented with complex CHD involving the right heart structures. For variant detection, we employed whole-genome single-nucleotide polymorphism (SNP) microarray and family-based whole-exome sequencing (WES) studies. Proband A is a full-term infant who was admitted to the neonatal intensive care unit (NICU) at five days of life for pulmonary valve stenosis (PVS). Genomic studies revealed a normal SNP microarray; however, quad WES analysis identified a novel heterozygous [Chr20:g.61041597C>G (p.Arg237Pro)] variant in the GATA5 gene. Further analysis confirmed that the novel variant was inherited from the mother but was absent in the father and the maternal uncle with a history of heart murmur. Proband B was born prematurely at 35 weeks gestation with a prenatally diagnosed complex CHD. A postnatal evaluation revealed right-sided heart defects including pulmonary atresia with intact ventricular septum (PA/IVS), right ventricular hypoplasia, tricuspid valve hypoplasia, hypoplastic main and bilateral branch pulmonary arteries, and possible coronary sinusoids. Cardiac catheterization yielded anatomy and hemodynamics unfavorable to repair. Hence, heart transplantation was indicated. Upon genomic testing, a normal SNP microarray was observed, while trio WES analysis identified a novel heterozygous [Chr18:c.1757C>T (p.Pro586Leu)] variant in the GATA6 gene. This variant was inherited from the father, who carries a clinical diagnosis of tetralogy of Fallot. These findings provide new insights into novel GATA5/6 variants, elaborate on the genotypic and phenotypic association, and highlight the critical role of GATA5 and GATA6 transcription factors in a wide spectrum of right-sided CHDs.

Monascus is a widely used natural microorganism in our country, which can produce useful secondary metabolites. Studies have shown that the nitrogen source directly affects the growth, reproduction, and secondary metabolites of Monascus. As a global transcriptional regulator of nitrogen metabolism, MareA gene is involved in the regulation of secondary metabolism. In this study, we found the MareA gene that is highly homologous to the AreA gene sequence, and used MareA to obtain ΔMareA and OE-MareA. Three strains were cultured with glutamine, urea, NaNO3, and (NH4)2SO4 nitrogen sources. The Monascus pigments and related genes were analyzed by solid-state fermentation under different nitrogen sources. The results showed that the pigment production of the ΔMareA decreased, but the OE-MareA did the opposite. The secondary metabolites of the three strains were analyzed by HPLC and expression level of pigment biosytnthesis gene was determined by RT-qPCR. The relative expression levels of four key Monascus pigment genes in ΔMareA were significantly upregulated in mppE gene, but downregulated in MpPKS5, mppG, and mppD genes. Monascus pigment genes were increased in OE-MareA. In terms of growth regulation, the expression of VosA and LaeA genes was significantly reduced in ΔMareA, while OE-MareA significantly promoted the expression of GprD genes. The pigment production and gene expression in ΔMareA were significantly lower than that of C100, while the opposite was true of OE-MareA when NaNO3 was added to the culture medium. In conclusion, MareA gene had different regulatory effects on Monascus growth and pigments metabolism under different nitrogen sources.

GATA binding protein 3 (GATA3), a member of the GATA family transcription factors, is a key player in various physiological and pathological conditions. It is known for its ability to bind to the DNA sequence "GATA", which enables its key role in critical processes in multiple tissues and organs including the immune system, endocrine system, and nervous system. GATA3 also modulates cell differentiation, proliferation, and apoptosis via controlling gene expression. In physiological instances, GATA3 is crucial for maintaining immunological homeostasis by mediating the development of naïve T cells into T helper 2 (Th2). In addition, GATA3 has been demonstrated to play a variety of cellular roles in the growth and maintenance of mammary gland, neuronal, and renal tissues. Conversely, the presence of impaired GATA3 is associated with a variety of diseases, including neurodegenerative diseases, autoimmune diseases, and cancers. Additionally, the altered expression of GATA3 contributes to the worsening of disease progression in hematological malignancies, such as T-cell lymphomas. Therefore, this review explores the multifaceted roles and signaling pathways of GATA3 in health and disease, with a particular emphasis on its potential as a therapeutic and prognostic target for the effective management of diseases.

Colorectal cancer (CRC) is among the lethal cancers, indicating the need for the identification of novel biomarkers for the detection of patients in earlier stages. RNA and microRNA sequencing were analyzed using bioinformatics and machine learning algorithms to identify differentially expressed genes (DEGs), followed by validation in CRC patients.

The genome-wide RNA sequencing of 631 samples, comprising 398 patients and 233 normal cases was extracted from the Cancer Genome Atlas (TCGA). The DEGs were identified using DESeq package in R. Survival analysis was evaluated using Kaplan-Meier analysis to identify prognostic biomarkers. Predictive biomarkers were determined by machine learning algorithms such as Deep learning, Decision Tree, and Support Vector Machine. The biological pathways, protein-protein interaction (PPI), the co-expression of DEGs, and the correlation between DEGs and clinical data were evaluated. Additionally, the diagnostic markers were assessed with a combioROC package. Finally, the candidate tope score gene was validated by Real-time PCR in CRC patients.

The survival analysis revealed five novel prognostic genes, including KCNK13, C1orf174, CLEC18A, SRRM5, and GPR89A. Thirty-nine upregulated, 40 downregulated genes, and 20 miRNAs were detected by SVM with high accuracy and AUC. The upregulation of KRT20 and FAM118A genes and the downregulation of LRAT and PROZ genes had the highest coefficient in the advanced stage. Furthermore, our findings showed that three miRNAs (mir-19b-1, mir-326, and mir-330) upregulated in the advanced stage. C1orf174, as a novel gene, was validated using RT-PCR in CRC patients. The combineROC curve analysis indicated that the combination of C1orf174-AKAP4-DIRC1-SKIL-Scan29A4 can be considered as diagnostic markers with sensitivity, specificity, and AUC values of 0.90, 0.94, and 0.92, respectively.

Machine learning algorithms can be used to Identify key dysregulated genes/miRNAs involved in the pathogenesis of diseases, leading to the detection of patients in earlier stages. Our data also demonstrated the prognostic value of C1orf174 in colorectal cancer.

The GATA gene family encodes highly conserved zinc-finger transcription factors that facilitate the development and function of multiple organ systems including the uterus. In the endometrium, GATA2 functions in a positive autoregulatory loop with the progesterone receptor (PGR) and colocalizes with PGR on chromatin to promote PGR transcriptional programs. GATA2 also has PGR-independent functions that maintain endometrial cell identity, and GATA2 transcripts reportedly are down-regulated in endometrial disorders including endometriosis. This event is accompanied by a reciprocal increase in GATA6. Here, we applied custom anti-GATA2 monoclonal antibodies and performed GATA2 immunohistochemistry (IHC) on patient endometrial tissues corresponding to proliferative, secretory, inactive, and hormone-treated endometrium, as well as endometriosis and endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN). We also performed IHC for the estrogen receptor, PGR, and GATA6 in relevant groups. The results reveal a tight correlation between GATA2 and PGR expression in the glandular and stromal cells of benign endometrium. GATA2 expression is markedly reduced in stromal but not glandular cells in endometriosis and EAH/EIN. This reduction in GATA2 expression does not lead to a detectable increase in GATA6 expression in endometriosis. Although average glandular GATA2 expression was preserved in endometriosis and EAH/EIN cases, its expression was decoupled from PGR, implying that alternative pathways regulate GATA2 levels in these disorders. Our findings indicate that GATA2 dysregulation is a feature of endometriosis and EAH/EIN, and support a model whereby loss of stromal GATA2 in these disorders contributes to their progesterone insensitivity.

Gastric cancer (GC) is an asymptomatic malignancy in early stages, with an invasive and cost-ineffective diagnostic toolbox that contributes to severe global mortality rates on an annual basis. Ectopic expression of the lineage survival transcription factors (LS-TFs) GATA4 and 6 promotes stomach oncogenesis. However, LS-TFs also govern important physiological roles, hindering their direct therapeutic targeting. Therefore, their downstream target genes are particularly interesting for developing cancer-specific molecular biomarkers or therapeutic agents. In this work, we couple inducible knockdown systems with chromatin immunoprecipitation and RNA-seq to thoroughly detect and characterize direct targets of GATA-mediated transcriptional regulation in gastric cancer cells. Our experimental and computational strategy provides evidence that both factors regulate the expression of several coding and non-coding RNAs that in turn mediate for their cancer-promoting phenotypes, including but not limited to cell cycle, apoptosis, ferroptosis, and oxidative stress response. Finally, the diagnostic and prognostic potential of four metagene signatures consisting of selected GATA4/6 target transcripts is evaluated in a multi-cancer panel of ~7000 biopsies from nineteen tumor types, revealing elevated specificity for gastrointestinal tumors. In conclusion, our integrated strategy uncovers the landscape of GATA-mediated coding and non-coding transcriptional regulation, providing insights regarding their molecular and clinical function in gastric cancer.

Gabapentin (GBP), an antiepileptic drug to treat epilepsy and neuropathic pain, has become an emerging pollutant in aquatic environments. Previous results suggested that GBP can cause a potential toxicity on the heart development of zebrafish but its cardiovascular effects are still not clear. In the current study, zebrafish embryos were exposed to GBP at environmental relevant concentrations (0, 0.1, 10 and 1000 μg/L) to assess its impact on cardiovascular systems during the early life stage of zebrafish. GBP exposure induced an increase in heartbeat rate and blood flow. The development of blood vessels was also affected with the vascular width significantly decreased at 10 μg/L and higher concentration of GBP. GBP exposure led to an abnormal vascular development by inhibiting the expression of relevant genes (flk1, vegfr-3, gata1, vegfα, and vegfr-2). Furthermore, GBP at 0.1 μg/L elevated the levels of reactive oxygen species and antioxidant enzyme. The vascular cell apoptosis was promoted through genes like p53, bad, and bcl2. However, these adverse effects were reversible with the antioxidant N-acetyl-L-cysteine, highlighting the crucial role of oxidative damage in GBP induced vascular toxicity. This research offers new perspectives on the adverse outcome pathways of antiepileptic drugs in non-target aquatic organisms.

Arsenic-induced diabetes, despite being a relatively newer finding, is now a growing area of interest, owing to its multifaceted nature of development and the diversity of metabolic conditions that result from it, on top of the already complicated manifestation of arsenic toxicity. Identification and characterization of the common and differentially affected cellular metabolic pathways and their regulatory components among various arsenic and diabetes-associated complications may aid in understanding the core molecular mechanism of arsenic-induced diabetes. This study, therefore, explores the effects of arsenic on human cell lines through 14 transcriptomic datasets containing 160 individual samples using in silico tools to take a systematic, deeper look into the pathways and genes that are being altered. Among these, we especially focused on the role of transcription factors due to their diverse and multifaceted roles in biological processes, aiming to comprehensively investigate the underlying mechanism of arsenic-induced diabetes as well as associated health risks. We present a potential mechanism heavily implying the involvement of the TGF-β/SMAD3 signaling pathway leading to cell cycle alterations and the NF-κB/TNF-α, MAPK, and Ca2+ signaling pathways underlying the pathogenesis of arsenic-induced diabetes. This study also presents novel findings by suggesting potential associations of four transcription factors (NCOA3, PHF20, TFDP1, and TFDP2) with both arsenic toxicity and diabetes; five transcription factors (E2F5, ETS2, EGR1, JDP2, and TFE3) with arsenic toxicity; and one transcription factor (GATA2) with diabetes. The novel association of the transcription factors and proposed mechanism in this study may serve as a take-off point for more experimental evidence needed to understand the in vivo cellular-level diabetogenic effects of arsenic.

The online version contains supplementary material available at 10.1007/s43188-024-00255-y.

SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain.

Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes.

The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype.

The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids.

We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

The functional role of long noncoding RNAs in the endothelium is highly diverse. Among their many functions, regulation of transcription factor activity and abundance is one of the most relevant. This review summarizes the recent progress in the research on the lncRNA-transcription factor axes and their implications for the vascular endothelium under physiological and pathological conditions. The focus is on transcription factors critical for the endothelial response to external stressors, such as hypoxia, inflammation, and shear stress, and their lncRNA interactors. These regulatory interactions will be exemplified by a selected number of lncRNAs that have been identified in the endothelium under physiological and pathological conditions that are influencing the activity or protein stability of important transcription factors. Thus, lncRNAs can add a layer of cell type-specific function to transcription factors. Understanding the interaction of lncRNAs with transcription factors will contribute to elucidating cardiovascular disease pathologies and the development of novel therapeutic approaches.

Mutations in GATA6 are associated with congenital heart disease, most notably conotruncal structural defects. However, how GATA6 regulates cardiac morphology during embryogenesis is undefined. We used knockout and conditional mutant zebrafish alleles to investigate the spatiotemporal role of gata6 during cardiogenesis. Loss of gata6 specifically impacts atrioventricular valve formation and recruitment of epicardium, with a prominent loss of arterial pole cardiac cells, including those of the ventricle and outflow tract. However, there are no obvious defects in cardiac progenitor cell specification, proliferation or death. Conditional loss of gata6 starting at 24 h is sufficient to disrupt the addition of late differentiating cardiomyocytes at the arterial pole, with decreased expression levels of anterior secondary heart field (SHF) markers spry4 and mef2cb. Conditional loss of gata6 in the endoderm is sufficient to phenocopy the straight knockout, resulting in a significant loss of ventricular and outflow tract tissue. Exposure to a Dusp6 inhibitor largely rescues the loss of ventricular cells in gata6-/- larvae. Thus, gata6 functions in endoderm are mediated by FGF signaling to regulate the addition of anterior SHF progenitor derivatives during heart formation.

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte's fertilization, the embryo's pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients.

As caretakers of the hematopoietic system, hematopoietic stem cells assure a lifelong supply of differentiated populations that are responsible for critical bodily functions, including oxygen transport, immunological protection and coagulation. Due to the far-reaching influence of the hematopoietic system, hematological disorders typically have a significant impact on the lives of individuals, even becoming fatal. Hematopoietic cell transplantation was the first effective therapeutic avenue to treat such hematological diseases. Since then, key use and manipulation of hematopoietic stem cells for treatments has been aspired to fully take advantage of such an important cell population. Limited knowledge on hematopoietic stem cell behavior has motivated in-depth research into their biology. Efforts were able to uncover their native environment and characteristics during development and adult stages. Several signaling pathways at a cellular level have been mapped, providing insight into their machinery. Important dynamics of hematopoietic stem cell maintenance were begun to be understood with improved comprehension of their metabolism and progressive aging. These advances have provided a solid platform for the development of innovative strategies for the manipulation of hematopoietic stem cells. Specifically, expansion of the hematopoietic stem cell pool has triggered immense interest, gaining momentum. A wide range of approaches have sprouted, leading to a variety of expansion systems, from simpler small molecule-based strategies to complex biomimetic scaffolds. The recent approval of Omisirge, the first expanded hematopoietic stem and progenitor cell product, whose expansion platform is one of the earliest, is predictive of further successes that might arise soon. In order to guarantee the quality of these ex vivo manipulated cells, robust assays that measure cell function or potency need to be developed. Whether targeting hematopoietic engraftment, immunological differentiation potential or malignancy clearance, hematopoietic stem cells and their derivatives need efficient scaling of their therapeutic potency. In this review, we comprehensively view hematopoietic stem cells as therapeutic assets, going from fundamental to translational.

GATA-binding protein 4 (GATA4) is recognized for its significant roles in embryogenesis and various cancers. Through bioinformatics and clinical data, it appears that GATA4 plays a role in breast cancer development. Yet, the specific roles and mechanisms of GATA4 in breast cancer progression remain elusive. In this study, we identify GATA4 as a tumor suppressor in the invasion and migration of breast cancer. Functionally, GATA4 significantly reduces the transcription of MMP9. On a mechanistic level, GATA4 diminishes MMP9 transcription by interacting with p65 at the NF-κB binding site on the MMP9 promoter. Additionally, GATA4 promotes the recruitment of HDAC1, amplifying the bond between p65 and HDAC1. This leads to decreased acetylation of p65, thus inhibiting p65's transcriptional activity on the MMP9 promoter. Moreover, GATA4 hampers the metastasis of breast cancer in vivo mouse model. In summary, our research unveils a novel mechanism wherein GATA4 curtails breast cancer cell metastasis by downregulating MMP9 expression, suggesting a potential therapeutic avenue for breast cancer metastasis.

Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by developmental hierarchical phenotypic heterogeneity, therapy resistance and recurrent growth. Neural stem cells (NSCs) from human central nervous system (CNS), and glioblastoma stem cells from patient-derived GBM (pdGSC) samples were cultured in both 2D well-plate and 3D monoclonal neurosphere culture system (pdMNCS). The pdMNCS model shows promise to establish a relevant 3D-tumor environment that maintains GBM cells in the stem cell phase within suspended neurospheres.

Utilizing the pdMNCS, we examined GBM cell-lines for a wide spectrum of developmental cancer stem cell markers, including the early blastocyst inner-cell mass (ICM)-specific Nanog, Oct3/4,B, and CD133.

We observed that MNCS epigenotype is recapitulated using gliomasphere-derived cells. CD133, the marker of GSC is robustly expressed in 3D-gliomaspheres and localized within the plasma membrane compartment. Conversely, gliomasphere cultures grown in conventional 2D culture quickly lost CD133 expression, indicating its variable expression is dependent on cell-culture conditions. Incomplete differentiation of cytoskeleton microtubules and intermediate filaments (IFs) of patient derived cells, similar to commercially available GBM cell lines, was seen. Subsequently, in order to determine whether Oct3/4 it was necessary for CD133 expression and cancer stemness, we transfected 2D and 3D culture with siRNA against Oct3/4 and found a significant reduction in gliomasphere formation.

These results suggest that expression of Oct3/4,A- and CD133 suppress differentiation of GSCs.

Osteogenesis is a complex multilevel process regulated by multiple genes. The GATA binding protein 4 (GATA4) gene has been extensively studied for its pivotal role in bone genesis and bone differentiation. However, its relationship with the growth traits of Shaanbei white cashmere (SBWC) and Guizhou black (GB) goats remains unclear. This work aims to investigate the potential influence of genetic mutations in the GATA4 gene on the growth traits goats. Thus, two Insertion/deletion (InDel) polymorphisms (8-bp-InDel and 9-bp-InDel) were screened and detected in a total of 1161 goats (including 980 SBWC goats and 181 GB goats) using PCR and agarose gel electrophoresis. The analyses revealed that there were two genotypes (ID and DD) for these two loci. In SBWC goats, 8-bp-InDel and 9-bp-InDel loci were significantly associated with heart girth (HG) and hip width (HW). Notably, individuals with DD genotype of 8-bp-InDel locus were superior while those with DD genotype of 9-bp-InDel locus were inferior. Correlation analyses of the four combined genotypes revealed significant associations with cannon circumference (CC), body height (BH), HG and HW. This work provides a foundation for the application of molecular marker-assisted selection (MAS) in goat breeding programs. Furthermore, the findings highlight the potential of the GATA4 gene and its genetic variations as valuable indicators for selecting goats with desirable growth traits.

Monogenic diabetes caused by GATA6 mutations were almost described as neonatal diabetes, and the phenotypic spectrum has expanded since then. Our study underscores the broad phenotypic spectrum by reporting a de novo GATA6 mutation in a family. Furthermore, we reviewed related literature to summarize the clinical and genetic characteristics of monogenic diabetes with GATA6 mutations (n = 39) in order to improve clinicians' understanding of the disease. We conclude that the GATA6 missense mutation (c. 749G > T, p. Gly250Val) is not reported presently, characterized by adult-onset diabetes with pancreatic dysplasia and located in transcriptional activation region. Carries with GATA6 mutations (n = 55) have a variable spectrum of diabetes, ranging from neonatal (72.7%), childhood-onset (20%) to adults-onset (7.5%). 83.5% of patients with abnormal pancreatic development. Heart and hepatobillary defects are the most common abnormalities of extrapancreatic features. Most mutations with GATA6 are loss of function (LOF, 71.8%) and located in functional region. Functional studies mostly support loss-of-function as the pathophysiological mechanism. In conclusion, there are various types of diabetes with GATA6 mutations, which can also occur in adult diabetes. Phenotypic defects with GATA6 mutations are most frequently malformations of pancreas and heart. This highlights the importance of comprehensive clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.

Transcription factors (TFs) play a crucial role in regulating the dynamic and precise patterns of gene expression required for the initial specification of endothelial cells (ECs), and during endothelial growth and differentiation. While sharing many core features, ECs can be highly heterogeneous. Differential gene expression between ECs is essential to pattern the hierarchical vascular network into arteries, veins and capillaries, to drive angiogenic growth of new vessels, and to direct specialization in response to local signals. Unlike many other cell types, ECs have no single master regulator, instead relying on differing combinations of a necessarily limited repertoire of TFs to achieve tight spatial and temporal activation and repression of gene expression. Here, we will discuss the cohort of TFs known to be involved in directing gene expression during different stages of mammalian vasculogenesis and angiogenesis, with a primary focus on development.

During embryonic development, the cardiovascular system and the central nervous system exhibit a coordinated developmental process through intricate interactions. Congenital heart disease (CHD) refers to structural or functional abnormalities that occur during embryonic or prenatal heart development and is the most common congenital disorder. One of the most common complications in CHD patients is neurodevelopmental disorders (NDD). However, the specific mechanisms, connections, and precise ways in which CHD co-occurs with NDD remain unclear. According to relevant research, both genetic and non-genetic factors are significant contributors to the co-occurrence of sporadic CHD and NDD. Genetic variations, such as chromosomal abnormalities and gene mutations, play a role in the susceptibility to both CHD and NDD. Further research should aim to identify common molecular mechanisms that underlie the co-occurrence of CHD and NDD, possibly originating from shared genetic mutations or shared gene regulation. Therefore, this review article summarizes the current advances in the genetics of CHD co-occurring with NDD, elucidating the application of relevant gene detection techniques. This is done with the aim of exploring the genetic regulatory mechanisms of CHD co-occurring with NDD at the gene level and promoting research and treatment of developmental disorders related to the cardiovascular and central nervous systems.

The GATA family of genes plays various roles in crucial biological processes, such as development, cell differentiation, and disease progression. However, the roles of GATA in insects have not been thoroughly explored. In this study, a genome-wide characterization of the GATA gene family in the silkworm, Bombyx mori, was conducted, revealing lineage-specific expression profiles. Notably, GATA6 is ubiquitously expressed across various developmental stages and tissues, with predominant expression in the midgut, ovaries, and Malpighian tubules. Overexpression of GATA6 inhibits cell growth and promotes apoptosis, whereas, in contrast, knockdown of PARP mitigates the apoptotic effects driven by GATA6 overexpression. Co-immunoprecipitation (co-IP) has demonstrated that GATA6 can interact with Poly (ADP-ribose) polymerase (PARP), suggesting that GATA6 may induce cell apoptosis by activating the enzyme's activity. These findings reveal a dynamic and regulatory relationship between GATA6 and PARP, suggesting a potential role for GATA6 as a key regulator in apoptosis through its interaction with PARP. This research deepens the understanding of the diverse roles of the GATA family in insects, shedding light on new avenues for studies in sericulture and pest management.

Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an infrequent autosomal dominant genetic disorder caused by haploinsufficiency of the GATA binding protein 3 (GATA3) gene. In this report, we present a case study of a 6-year-old female patient manifesting seizures, tetany, hypoparathyroidism, and sensorineural hearing loss. A heterozygous variant, c.1050 + 2T>C, in the GATA3 gene was discovered by genetic testing. Moreover, a minigene splicing experiment revealed that the aforementioned variation causes incorrect splicing and premature cessation of protein synthesis. The clinical profile of the patient closely resembles the well-known phenomenology of HDR syndrome, supporting the association between the condition and the GATA3 variant. The challenges in early diagnosis highlight the importance of employing next-generation sequencing for timely detection of rare diseases. Additionally, this research contributes to a deeper understanding of the genotype-phenotype correlations in HDR syndrome, underscoring the critical need for improved diagnostic and therapeutic strategies.

Protein restriction (PR) leads to bone marrow hypoplasia with changes in stromal cellularity components of the extracellular matrix in hematopoietic stem cells (HSCs). However, the underlying signaling mechanisms are poorly understood. We hypothesize that PR impairs the HSC mitogen-activated protein kinase (MAPK) signaling pathway response activation. Our aim is to evaluate the activation of MAPK and interleukin-3 (IL-3) proteins in HSC to explain PR-induced bone marrow hypoplasia, which causes altered proliferation and differentiation. C57BL/6 male mice were subjected to a low-protein diet (2% protein) or normoproteic (12% protein). PKC, PLCγ2, CaMKII, AKT, STAT3/5, ERK1/2, JNK, and p38d phosphorylation were evaluated by flow cytometry, and GATA1/2, PU.1, C/EBPα, NF-E2, and Ikz-3 genes (mRNAs) assessed by quantitative real-time-polymerase chain reaction. Pathway proteins, such as PLCγ2, JAK2, STAT3/5, PKC, and RAS do not respond to the IL-3 stimulus in PR, leading to lower activation of ERK1/2 and Ca2+ signaling pathways, consequently lowering the production of hematopoietic transcription factors. Colony forming units granulocyte-macrophage and colony forming units macrophage formation are impaired in PR even after being stimulated with IL-3. Long-term hematopoietic stem cells, short-term hematopoietic stem cells, granulocyte myeloid progenitor, and megakaryocyte-erythroid progenitor cells were significantly reduced in PR animals. This study shows for the first time that activation of MAPK pathway key proteins in HSCs is impaired in cases of PR. Several pathway proteins, such as PLCγ2, JAK2, STAT3, PKC, and RAS do not respond to IL-3 stimulation, leading to lower activation of extracellular signal-regulated protein kinase 1/2 and consequently lower production of hematopoietic transcription factors GATA1/2, PU.1, C/EBPa, NF-E2, and Ikz3. These changes result in a reduction in colony-forming units, proliferation, and differentiation, leading to hypocellularity.

Medroxyprogesterone (MPA) has therapeutic effect on endometrial carcinoma (EC), while it could promote the carcinogenesis of breast cancer (BC) by activating receptor activator of NF-kB ligand (RANKL). However, the selective mechanism of MPA in endometrium and breast tissue remains obscure. Multiomics analysis of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were performed in cell lines derived from endometrial cancer and mammary tumor to screen the differential co-regulatory factors of progesterone receptor (PR). Dual-luciferase assays and ChIP-PCR assays were used to validate the transcriptional regulation. Co-immunoprecipitation (Co-IP) and immunofluorescence assays were carried out to explore molecular interactions between PR, the cofactor transcriptional repressor GATA binding 1 (TRPS1), and histone deacetylase 2 (HDAC2). Subsequently, human endometrial cancer/breast cancer xenograft models were established to investigate the regulation effect of cofactor TRPS1 in vivo. In the current study, we found that MPA downregulated RANKL expression in a time- and dose-dependent manner in EC, while had the opposite effect on BC. Then PR could recruit cofactor TRPS1 to the promoter of RANKL, leading to histone deacetylation of RANKL to repress its transcription in EC, whereas MPA disassociated the PR/TRPS1/HDAC2 complex to enhance RANKL histone acetylation in BC. Therefore, TRPS1, the coregulator recruited by PR played a critical role in the selective mechanism of progesterone in EC and BC and could become a potential candidate for targeted therapy to improve the anticancer effect of MPA on EC and avoid its carcinogenic effect on BC.

Protein-DNA binding sites of ChIP-seq experiments are identified where the binding affinity is significant based on a given threshold. The choice of the threshold is a trade-off between conservative region identification and discarding weak, but true binding sites.

We rescue weak binding sites using MSPC, which efficiently exploits replicates to lower the threshold required to identify a site while keeping a low false-positive rate, and we compare it to IDR, a widely used post-processing method for identifying highly reproducible peaks across replicates. We observe several master transcription regulators (e.g., SP1 and GATA3) and HDAC2-GATA1 regulatory networks on rescued regions in K562 cell line.

We argue the biological relevance of weak binding sites and the information they add when rescued by MSPC. An implementation of the proposed extended MSPC methodology and the scripts to reproduce the performed analysis are freely available at https://genometric.github.io/MSPC/ ; MSPC is distributed as a command-line application and an R package available from Bioconductor ( https://doi.org/doi:10.18129/B9.bioc.rmspc ).