Search Results (285)

Neonatal Diabetes Mellitus (NDM) is a rare, heterogeneous monogenic disorder typically presenting within the first six months of life. Unlike type 1 or type 2 diabetes, NDM is caused by single-gene mutations that disrupt pancreatic β-cell function or development. With the advent of next-generation sequencing, the genetic spectrum of NDM has expanded significantly, necessitating a shift from symptomatic management to precision medicine. This narrative review summarizes the genetic basis and pathogenic mechanisms of NDM, categorizing them into three major pathways: (1) ATP-sensitive potassium (K_ATP) channelopathies (e.g., ABCC8, KCNJ11), where gain-of-function mutations inhibit insulin secretion; (2) Transcription factor defects (e.g., GLIS3, PAX6, GATA6), which impair pancreatic development and often present with syndromic features; and (3) Endoplasmic reticulum (ER) stress-mediated β-cell apoptosis, exemplified by WFS1 mutations. Furthermore, we highlight the clinical complexity of these mutations, including the “biphasic phenotype” observed in ABCC8 and HNF1A variants. Understanding these molecular mechanisms is critical for clinical decision-making. We discuss the transformative impact of genetic diagnosis in treatment, particularly the successful transition from insulin to oral sulfonylureas in patients with K_ATP channel mutations, and emphasize the importance of early genetic testing to optimize glycemic control and prevent complications. Full article

Background/Objectives: GATA-binding protein 3 (GATA-3) is a crucial transcription factor that drives type 2 immune responses, and it is actively involved in allergic conditions such as asthma, allergic rhinitis (AR), and atopic dermatitis (AD). However, the molecular mechanisms GATA-3 uses to modulate immune responses and its potential therapeutic targeting are not fully understood. This systematic review aimed to summarize studies on the role of GATA-3 in immune responses, particularly in allergic diseases, and evaluate GATA-3’s potential as a therapeutic target. Methods: We searched PubMed, Scopus, Web of Science, Cochrane, and Science Direct for studies published before April 2025. Articles were sifted through using predefined criteria, and risk of bias was measured with RoB 2 for clinical trials and SYRCLE for animal models and in vitro studies; evidence was graded using the GRADE system. Results: Twenty-nine eligible studies reported that GATA-3 is a key regulator of Th2 and ILC2 differentiation, promoting the production of IL-4, IL-5, and IL-13. Animal models and in vitro studies demonstrated its role in exacerbating allergic inflammation and highlighted the promise of targeting strategies such as DNAzymes and nanocapsules. Clinical trials showed that targeting GATA-3, particularly with DNAzymes, can reduce allergic responses in asthma. Conclusions: GATA-3’s role in driving allergic inflammation through Th2 and ILC2 pathways suggests it as a promising therapeutic target. Understanding its broader regulatory mechanisms is imperative for designing effective GATA-3 targeting-based therapies. Full article

Obesity plays a crucial role in the progression of insulin resistance and type 2 diabetes which are related to inflammation and liver disease. GATA-3 is a transcription factor that is involved in adipogenesis and inflammation. Therefore, it could be a potential therapeutic target for obesity-associated metabolic disorders. This study aimed to examine the effects of GATA-3 suppression on body weight, fat depot redistribution, liver histopathology, and inflammatory markers in transgenic db/db obese mice. Male db/db mice received subcutaneous injections of GATA-3-specific DNAzyme (hgd40; 10 or 100 µg/mL), pioglitazone (as a positive control), or vehicle only (as a negative control), twice weekly for two weeks. Body weight, organ weights, liver histopathology, mRNA expression of selected genes and serum cytokine levels were assessed. GATA-3 expression was not region specific, and its suppression did not significantly affect fat depot distribution or organ weights. However, the low dose of hgd40 accelerated body weight gain transiently. It also increased Il10 mRNA expression in the liver and significantly increased IL-10 protein concentration in the serum. In addition, a high dose of hgd40 resulted in a marked decrease in hepatocyte ballooning degeneration. These findings suggest that GATA-3 suppression may modulate inflammation and liver injury in obesity, warranting further investigation into its therapeutic potential for obesity-related metabolic disorders. Full article

Background: Maternal aging progressively compromises oocyte competence, yet the precise molecular trajectory across the reproductive lifespan remains insufficiently defined. Methods: Here, we mapped the transcriptomic landscape of mouse germinal vesicle (GV) oocytes across three distinct reproductive stages: post-pubertal peak fertility (Young, 8 weeks), fertility decline (Middle, 12 months), and reproductive senescence (Old, 18 months). Results: Our bioinformatic analyses reveal that oocyte aging follows a biphasic nonlinear trajectory. The transition from Young to Middle age marked the most profound period of transcriptional destabilization, characterized by 1197 DEGs and extensive perturbation of metabolic and signaling networks. To elucidate the regulatory drivers of this early drift, we performed transcription factor binding site (TFBS) analysis, which identified massive regulatory potential involving master regulators such as LHX8, MYC, and GATA4. Interestingly, despite the predicted extensive TF–target interactions, the mRNA expression levels of these TFs remained stable across age groups. This discrepancy suggests that the observed transcriptional dysregulation is likely associated by age-associated epigenetic modifications that alter chromatin accessibility or binding efficiency, rather than TF depletion. In the subsequent transition from Middle to Old age, the landscape shifted from active perturbation to systemic collapse. This late stage was characterized by mitochondrial respiratory dysfunction and severe proteostatic stress. Conclusions: Colectively, our findings define oocyte aging as a biphasic transition from compensatory resistance to systemic collapse. We identify midlife as the critical inflection point of regulatory remodeling, followed by terminal network exhaustion in senescence. This framework provides a molecular foundation for therapeutic and rejuvenation strategies aimed at mitigating age-associated infertility. Full article

GATA transcription factors, defined by their zinc finger DNA-binding domains, are central regulators of tissue development. They modulate gene expression by activating or repressing transcription, thereby coordinating cellular differentiation and cell cycle exit to maintain homeostasis. In progenitor cells, GATA factors promote proliferation, whereas in differentiating cells, they drive maturation and induce cell cycle arrest. Dysregulation of GATA factors has been linked to tumorigenesis and contributes significantly to cancer progression and metastasis. Mutations in GATA factor genes correlate with poor prognosis in multiple cancers, where they influence key oncogenic processes, including sustained proliferative signaling, activation of epithelial–mesenchymal transition, angiogenesis, resistance to cell death, and immune escape. Importantly, their context-dependent roles across tumor types highlight the complexity of their functions in malignancies. Meanwhile, non-coding RNAs have emerged as critical regulators of gene expression, acting as either tumor suppressors or oncogenes by modulating chromatin dynamics, transcription factor activity, and mRNA stability. Despite this, the regulation of GATA transcriptional activity by non-coding RNAs remains largely unexplored. This review highlights the role of GATA factors in regulating EMT and metastasis and focuses on the interplay between non-coding RNAs and GATA transcription factors in cancer progression, proposing a novel regulatory axis with potential implications for biomarker discovery and therapeutic targeting. Full article

Mustard (Brassica juncea), an essential leaf and oil crop in China, exhibits notable yield potential and adaptability, both of which are influenced by the morphology of the leaf margin. Despite its agronomic importance, the genetic regulatory mechanisms governing this trait remain poorly understood, posing a challenge to molecular breeding efforts. In this study, mustard varieties with lobed and non-lobed leaf margins were used to systematically investigate the genetic basis of leaf margin differentiation through BSA-seq, RNA-seq, and bioinformatics analyses. BSA-seq screening identified four LMI1 homologous genes, including BjuOA10G33260, which may fissure the leaf margin by suppressing cytokinin signaling. RNA-seq analysis revealed significant enrichment of ethylene and growth hormone pathways during key stages of leaf development (at 12 days post-sowing). Integrated analysis of BSA-seq and RNA-seq data identified 15 genes involved in leaf morphogenesis, including BjuOB05G34700 (ADF4, an actin depolymerization factor), BjuOA08G35830 (GATA transcription factor 11), BjuOA09G42060 (ERF transcription factor), and BjuOA07G29650 (GATA transcription factor). Notably, BjuOA10G30380 (TGA2) and BjuOA10G34680 (LAX1) may regulate cytoskeletal dynamics and hormonal signaling, contributing to the development of leaf morphology. This study presents the first molecular network regulating the morphogenesis of the leaf edge in mustard, offering a theoretical foundation and valuable genetic resources for breeding new varieties with optimized leaf architecture. Full article

Mutations in the POU1F1 gene cause defects in the expression of the genes encoding thyroid-stimulating hormone (TSH)-β subunit, growth hormone (GH), and prolactin (PRL). Here, we characterized 15 missense and nonsense mutations. Protein stability was reduced in the P14L, P24L, F135C, K145X, F233S and E250X mutants. Transactivation by 15 mutants in the TSHβ promoter was moderately correlated with that of the PRL promoter. Based on their transcriptional activity, we classified them into three groups: group I, equivalent to the wild type; group II, partial; and group III, substantially lost. A review of case reports on four patients with group II mutations revealed that TSH deficiency manifested after recombinant GH therapy. A transcription factor, GATA2, is the main activator in the TSHβ gene, while POU1F1 protects its function from inhibition by the suppressor region (SR). We found that the SR is critical for the pathogenesis of TSH deficiency. The transactivation of the TSHβ promoter by the K216E mutant was equivalent to that of wild-type POU1F1; however, that of the PRL promoter was low, while the opposite was found in the R271W mutant. The functional property of K216E suggests that the interaction of POU1F1 with GATA2 may not always be necessary for the activation of the TSHβ promoter. Full article

Background: Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. Methods: A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall’s Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. Results: CD8⁺ T cells expressing a specific epitope of the ASFV p72 protein (ACD8⁺) accounted for 41% of the total CD8⁺ T cells in peripheral blood. A total of 2062 transcripts were identified as differentially expressed across the nine pigs (q-value < 1 × 10⁻⁸). Differential expression levels of the target genes for MECP2, ETS1, ZBTB33, ELK4, and E2F4 were significantly correlated with their TF binding potential (p < 0.05). Six SNPs were identified in the promoter region of ELK4. Analysis of the 112-pig population revealed that SNPs at S.-404A>G and S.-668C>T loci were significantly associated with ACD8⁺ levels (q-value < 0.01). Individuals with the AA genotype at S.-404A>G had significantly higher ACD8⁺ counts compared to those with AG and GG genotypes (q-value < 0.05). At the S.-668C>T locus, ACD8⁺ levels were highest in the CC genotype, followed by CT and TT genotypes, with CC showing notably higher ACD8⁺ counts (q-value < 0.05). Notably, the S.-404A>G site overlaps with potential binding sites for TFs FOXA2, GATAs, and TRPS1, while the S.-668C>T site lies within the binding regions for NR1H3, RARA, VDR, and NR1I3. Conclusion: These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Full article

Teleost fish are the first evolutionary group to exhibit an innate and adaptive immune system. Within the mechanisms of adaptive immunity, fish possess, among others, T-helper cells (CD4-like) and their differentiation machinery, regulated by the master transcription factors T-bet, GATA3, Foxp3, and RORγ. Many studies support the existence of a non-neuronal cholinergic system involved in the immune response, named after the ability of leukocytes to synthesize de novo acetylcholine (ACh). Organophosphorus pesticides (OPs), such as diazoxon (DXN), are examples of compounds that act as cholinergic disruptors with immunotoxic effects. The present study aimed to evaluate the expression of transcription factors in leukocytes (spleen mononuclear cells, SMNCs) of Nile tilapia by modulating cholinergic pathways in immune cells using agonists, antagonists, and diazoxon (DXN), an anticholinesterase substance. The obtained data showed a significant increase in RORγ mRNA expression upon stimulation with the nicotinic agonist, whereas activation of the muscarinic receptor with its agonist increased T-bet mRNA expression. An alteration in RORγ expression levels induced by DXN exposure was also observed. The results suggest a probable directing of the immune response towards a pro-inflammatory profile orchestrated mainly by RORγ and T-bet transcription factors in response to cholinergic stimuli. Full article

The transcription factor homeodomain-only protein X (HOPX) is the smallest member of the homeodomain protein family. Lacking a DNA-binding domain, it acts as a co-effector, interacting with other transcription factors such as serum response factor (SRF) and GATA-binding factor 6 (GATA6) to regulate the differentiation and development of the heart and lung. HOPX exerts a tumor-suppressive function in various types of epithelial-derived carcinoma, while it promotes oncogenic effects in mesenchymal-derived sarcoma, indicating a distinct role of HOPX in the two major types of the malignancy. In addition, accumulating evidence shows that HOPX is expressed in the immune system and involved in the differentiation of immune cells. Recently, the emerging role of HOPX in metabolism has gained attention. This review describes the identification of HOPX in various tissues and discusses its role in carcinogenesis, as well as its functions in tissue differentiation, lipid metabolism, immunity, and the tumor microenvironment. The participation of HOPX in carcinogenesis and immunity implies that it may serve as a potential enhancer in tumor immunotherapy. Full article

Background: Ulcerative colitis (UC), a chronic and relapsing form of inflammatory bowel disease (IBD), arises from a multifactorial interplay of genetic predisposition, immune dysregulation, and environmental triggers. Despite advances in understanding UC pathogenesis, the identification of reliable biomarkers and key regulatory genes remains essential for unraveling disease mechanisms. Such insights are crucial for improving diagnostic precision and developing personalized therapeutic strategies. Methods: In this study, gene expression profiles from publicly available microarray and RNA-sequencing datasets were systematically analyzed using advanced bioinformatics tools. Differentially expressed genes (DEGs) were identified through statistical comparisons, and functional enrichment analyses were performed to explore their biological relevance. A total of 141 overlapping DEGs were extracted from three GEO datasets, and 20 key DEGs were further prioritized via protein–protein interaction (PPI) network construction. Hub genes, relevant signaling pathways, associated transcription factors (TFs), and microRNAs (miRNAs) linked to disease progression were identified. Potential therapeutic compounds were also predicted through computational drug–gene interaction analysis. Results: The analysis revealed a panel of novel biomarkers-TLR2, IFNG, CD163, CXCL9, CCL4, PRF1, TLR8, ARG1, LILRB2, FPR2, and PPARG-that function as key hub genes implicated in ulcerative colitis (UC) pathogenesis. These genes were associated with critical biological processes including signal transduction, inflammatory and immune responses, proteolysis, lipid transport, and cholesterol/triglyceride homeostasis. Furthermore, transcription factors (FOXC1, GABPA, GATA2, SUPT5H) and microRNAs (hsa-miR-34a-5p, hsa-miR-335-5p, hsa-miR-24-3p, hsa-miR-23a-5p, hsa-miR-26a-5p) revealed key regulatory networks influencing post-transcriptional gene regulation. Molecular docking analysis predicted Apremilast and Golotimod as promising therapeutic candidates for UC intervention. Conclusions: In conclusion, this study enhances our understanding of ulcerative colitis pathogenesis by identifying key biomarkers and therapeutic targets, paving the way for future advancements in personalized diagnosis and treatment strategies. Full article

Background: Sodium/iodide symporter (NIS) is a membrane protein involved in iodide transport into cells, making it a key component of thyroid physiology and radioiodine therapy for thyroid cancer. Although NIS is expressed in many extrathyroidal tissues, including breast tumors, its functional role and prognostic significance in these contexts remain a subject of active investigation. Understanding the mechanisms regulating NIS, its influence on cellular processes such as migration and metastasis, and its connection with transcription factors like FOXA1 could contribute to the development of new therapeutic strategies for breast cancer treatment. This study aims to investigate the correlation between sodium/iodide symporter (NIS) expression and response to neoadjuvant chemotherapy in patients with triple-negative breast cancer (TNBC). Methods: The current retrospective study included 161 TNBC patients who received neoadjuvant chemotherapy followed by mastectomy. NIS expression was assessed via immunohistochemistry, graded semi-quantitatively from 0 to 3+. The Residual Cancer Burden (RCB) scale was used to evaluate the response to chemotherapy. Statistical analysis included Lilliefors tests and Kendall’s tau correlation coefficient. Publicly available Cancer Genome Atlas datasets were analyzed to assess the relationship between NIS and FOXA1 expression. Results: NIS immunopositivity was observed in 69.5% of TNBC samples compared to 63.3% GATA-3-positive and 31.0% of Mammaglobin-positive samples. While no significant correlation was found between NIS expression and age, TNM stage, or Ki-67, a statistically significant moderate positive correlation (τ = 0.481, p < 0.01) was identified between NIS expression and RCB index, indicating that higher NIS expression was associated with a poorer response to neoadjuvant chemotherapy. TCGA data analysis revealed a statistically significant increase in NIS mRNA expression in FOXA1-mutated TNBC samples compared to FOXA1-wild-type samples (p < 0.05). Younger patients exhibited higher Ki-67 levels (τ = −0.416, p < 0.05). Conclusions: Higher NIS expression correlates with chemoresistance to neoadjuvant chemotherapy in TNBC patients. This phenomenon may be linked to FOXA1 activity, suggesting that NIS may represent a potential biomarker for chemoresistance in TNBC. The inverse correlation between patient age and Ki-67 levels may be associated with a different mutational landscape in younger patients. Full article

Background/Objectives: GATA transcription factors play pivotal roles in regulating plant growth and development, physiological metabolism, and responses to environmental stress. However, research on GATA genes in sweetpotato remains limited. Methods: In this study, we identified 25 IbGATA genes in sweetpotato (Ipomoea batatas [Lam.] L.) through a genome-wide analysis. These genes were analyzed for their physicochemical properties, chromosomal localization, synteny, phylogenetic relationships, gene structure, promoter cis-elements, protein interaction networks, and expression profiles across various tissues and under drought stress. To elucidate the function of drought-resistant candidate genes, an in situ one-step transformation method was employed. Results: Sweetpotato GATA genes have a complex evolutionary history, including replication events, different selection pressures, and functional diversification. They may be involved in multiple plant stress signaling pathways. Furthermore, functional analysis revealed that IbGATA17 enhances drought tolerance in sweetpotato by promoting proline biosynthesis and reinforcing ROS scavenging capacity. Our findings provide novel insights into the roles of IbGATAs, particularly IbGATA17, in mediating drought-stress responses in sweetpotato. Conclusions: This study provides foundational insights into the GATA gene family in sweetpotato and reveals the pivotal role of IbGATA17 in simulated drought-stress response, providing a potential candidate gene for the development of drought-resistant varieties. Full article

MicroRNA (miRNA), as a key post-transcriptional regulatory factor, plays a crucial role in embryonic development. The coordination of endoderm cell convergence and cardiac precursor cell (CPC) migration is critical for cardiac tube fusion. Defects in endoderm can impair the normal migration of CPCs towards the midline, leading to cardia bifida. Although the role of the microRNA-183 family (miR-183, miR-96 and miR-182) in cardiovascular diseases has been reported, the mechanism by which they regulate early heart development remains unclear. In this study, we used zebrafish as a model to elucidate the roles of the microRNA-183 family in early heart development. miRNA mimics were injected into Tg (cmlc2: eGFP) and Tg (sox17: eGFP) transgenic embryos to overexpress the miR-183 family. The results showed that, at 36 hpf, single or co-injection of miR-183/96/182 mimics caused defects in endoderm convergence, with a hole in the endoderm, and a significant down-regulation of the endoderm marker gene sox32. Additionally, embryos with single or co-injection of miR-183/96/182 mimics exhibited cardia bifida and tail blisters, with significantly down-regulated expression levels of genes related to heart development, including cmlc2, vmhc, amhc, nppa, gata4, gata5, nkx2.5, bmp2b, and bmp4. The phenotype caused by overexpression of the miR-183 family is highly consistent with loss of the sphingosine 1-phosphate receptor S1Pr2. Bioinformatics analysis result found that miR-183 can bind to 3′-UTR of the s1pr2 to regulate its expression; overexpression of miR-183 led to a significant decrease in the expression of the s1pr2 gene. Dual luciferase assay results suggest that s1pr2 is a bona fide target of miR-183. In summary, the miR-183 family regulates endoderm convergence and cardiac precursor cell migration via the S1Pr2 signaling pathway. This study reveals that the miR-183 family is a key regulatory factor in endoderm convergence and cardiac precursor cell migration during the early zebrafish development, elucidating the molecular mechanisms underlying early cardiac precursor cell and endoderm cell movement. Full article

Seed storage proteins (SSPs) play a pivotal role in determining the development, quality, and nutritional value of rice seeds. In this study, we conducted a transcriptome-based correlation analysis to identify novel transcription factors (TFs) potentially involved in the biosynthesis and accumulation of SSPs. Our analysis revealed nine TFs—OsGATA8, OsMIF1, OsMIF2, OsGZF1, OsbZIP58, OsS1Fa1, OsS1Fa2, OsICE2, and OsMYB24—that exhibit strong co-expression with key SSP genes, including those encoding glutelin and prolamin. Gene expression profiling using quantitative RT-PCR and GUS reporter assays revealed that these TFs are predominantly expressed during seed development, with peak expression observed at 10 days after flowering (DAF). Promoter analysis further demonstrated an enrichment of seed-specific and hormone-responsive cis-regulatory elements, reinforcing the seed-preferential expression patterns of these TFs. Collectively, our findings identify a set of candidate TFs likely involved in SSP regulation and seed maturation, providing a foundation for the genetic enhancement of rice seed quality and nutritional content through targeted breeding and biotechnological approaches. Full article