Search Results (69)

The aryl hydrocarbon receptor (AHR) and the vitamin D receptor (VDR) were long regarded as independent transcription factors governing distinct physiology—xenobiotic sensing and calcium–vitamin D homeostasis, respectively. AHR, a basic helix–loop–helix/PAS protein, heterodimerizes with ARNT and binds xenobiotic response elements (XREs) to drive cytochrome P450 genes such as CYP1A1; VDR, a nuclear receptor activated by 1,25-dihydroxyvitamin D₃, heterodimerizes with RXR and binds vitamin D response elements (VDREs). Although their genes reside on separate chromosomes (AHR, Chr 7; VDR, Chr 12), an integrated view recognizes the two pathways as extensively cross-regulatory. This review synthesizes the molecular, immunological, and tissue-level evidence for VDR–AHR interplay. At the molecular level, the receptors cooperate at composite promoter architectures—most notably an everted-repeat VDRE positioned adjacent to an XRE in the CYP1A1 promoter—while AHR ligands reciprocally enhance CYP24A1-mediated catabolism of active vitamin D. Tryptophan metabolism provides a bidirectional hub: kynurenine and the UVB photoproduct FICZ serve as endogenous AHR ligands whose balance, modulated by VDR, shapes signaling output. The tumor suppressor p53 functions as a shared upstream regulator coupling genotoxic stress to both receptors, with convergence on the CDKN1A (p21) checkpoint. Functionally, AHR and VDR converge on the regulatory T cell (Treg)/Th17 axis to influence immune tolerance: sustained AHR activation by TCDD favors Foxp3⁺ Treg differentiation, transient FICZ-driven activation promotes Th17 responses, and VDR reinforces the tolerogenic arm while independently repressing IL-17. The receptors further cooperate in maintaining intestinal epithelial barrier integrity and NF-κB restraint, with parallel impairment in inflammatory bowel disease, and are co-activated in skin by solar UVB, which simultaneously generates vitamin D₃ and the AHR ligand FICZ within keratinocytes. In cancer, VDR acts as a tumor suppressor, AHR exhibits context-dependent pro- and anti-tumor roles, and a three-way AHR–VDR–p53 interaction—inverted by mutant p53—forms a critical regulatory node. Throughout, the direction and magnitude of cross-talk prove highly dependent on cell type, ligand identity and kinetics, and species—distinctions often underappreciated in the literature. Clarifying these context-specific determinants is essential for translating AHR–VDR cross-regulation into rational therapies in autoimmunity, mucosal inflammation, dermatology, and oncology. Full article

Bovine alphaherpesvirus 1 (BoHV-1) acute infection induces respiratory tract disorders and conjunctivitis and suppresses immune responses that may cause bacterial pneumonia. BoHV-1 infection establishes lifelong latency in sensory neurons in trigeminal ganglia (TG), the central nervous system, and certain cells in the pharyngeal tonsil. BoHV-1 is a chronic problem in the cattle industry because stress, including the synthetic corticosteroid dexamethasone, triggers reactivation from latency after an intravenous injection. The BoHV-1 immediate early transcription unit 1 (IEtu1) promoter drives expression of infected cell protein 0 (bICP0) and bICP4, two viral transcriptional regulators. Stress activates the glucocorticoid receptor (GR), and Krüppel-like factor 15 (KLF15) cooperatively transactivates the BoHV-1 IEtu1 promoter if both GR response elements (GREs) are intact. Since the bICP0 gene contains a separate early (E) promoter, we tested the hypothesis that GR+KLF family members transactivate the bICP0 E-promoter. GR+KLF4, both pioneer transcription factors, cooperatively stimulate bICP0 E-promoter activity in mouse neuroblastoma cells (Neuro-2A), and stimulate productive infection. Notably, the bICP0 E-promoter lacks GREs, suggesting that a novel mechanism triggers transactivation. CA motifs and C-rich Sp1 binding sites in bICP0 E-promoter sequences are crucial for transactivation and binding to GR and KLF4. Full article

Tree peony (Paeonia suffruticosa Andr.) is a traditional ornamental plant of high economic and cultural value, but its flower longevity is often limited by petal water loss. Cuticular wax serves as an essential barrier against non-stomatal water loss, and the AP2/EREBP (APETALA2/Ethylene-Responsive Element Binding Protein) transcription factor family is known to regulate wax biosynthesis. However, little information is available on the roles of AP2/EREBP genes in petal cuticle formation in tree peony. In this study, we performed transcriptome sequencing on petals of the tree peony cultivar ‘Bai Wang Shi Zi’ at three developmental stages (early, middle, and late). Using the assembled transcriptomic data, we identified 29 high-confidence AP2/EREBP family members, which were phylogenetically classified into AP2, ERF, and DREB subfamilies. Expression profiling revealed that 18 of these genes exhibited stage-specific expression patterns during petal development. Among them, two homologs of Arabidopsis SHN1 (SHINE 1) and WRI3 (WRINKLED 3), designated PsSHN1 and PsWRI3, showed peak expression at the middle stage. By co-expression analysis and phylogenetic comparison, three downstream candidate genes were identified and named PsCER2, PsKAS1, and PsLTPG1, based on their homology with known wax-related genes. Dual-luciferase reporter assays indicated that PsSHN1 and PsWRI3 can activate the promoters of PsCER2, PsKAS1, and PsLTPG1, suggesting a possible cooperative regulation of cuticle formation. Collectively, our findings provide promising candidate genes for prolonging floral lifespan by improving petal cuticular wax accumulation, and lay a preliminary foundation for molecular breeding and quality improvement of tree peony and other ornamental flowers. Full article

Erythropoiesis is tightly regulated by lineage-specific transcription factors that govern erythroid commitment, proliferation, and differentiation. A core erythroid transcriptional network, together with non-DNA-binding cofactors, occupies regulatory regions of genes essential for erythroid development. This process is further shaped by epigenetic mechanisms, including histone post-translational modifications and long-range chromatin interactions. CCCTC-binding factor (CTCF) is a multifunctional regulator with a central role in three-dimensional chromatin organization. Although CTCF has been implicated in hematopoietic differentiation and leukemogenesis, its specific function in erythropoiesis remains poorly defined. Here, we investigated the role of CTCF during erythroid differentiation using two complementary models: pluripotent K562 leukemia cells and primary human CD34⁺ hematopoietic stem/progenitor cells, each induced toward the erythroid lineage by distinct stimuli. In both systems, CTCF silencing impaired erythroid differentiation by repression of key erythroid transcription factor genes, including LMO2, KLF1, MYB, and ETS1. This repression was associated with enrichment of repressive histone marks at CTCF-binding sites within their regulatory regions. Moreover, CTCF cooperated with cohesin to establish and stabilize long-range chromatin interactions at these loci. These results provide new insight into how CTCF-dependent chromatin regulation contributes to normal erythroid development and suggest that perturbation of this regulatory axis may have implications for hematopoietic disorders and malignancies. Full article

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells. Full article

The nuclear membrane has emerged as a dynamic regulatory platform coordinating genome organization, mechanotransduction, and regulated cell death (RCD). Beyond its barrier function, the nuclear skeleton—comprising lamins, actin–myosin isoforms, nuclear matrix proteins, and the LINC complex—supports nuclear integrity and gene regulation. Recent evidence shows that type II membrane-bound bZIP transcription factors such as cAMP-responsive element-binding protein 3 (CREB3) and CREB3L1 localize to the inner nuclear membrane (INM), linking chromatin tethering with stress signaling. Their stress-induced cleavage by S1P/S2P disrupts chromatin anchoring and, in some contexts, triggers karyoptosis, a novel form of RCD defined by nuclear rupture. These findings position the nuclear envelope (NE) as a mechanosensitive signaling hub with direct implications for disease and therapy. In this review, we provide a comprehensive discussion on how type II membrane-bound bZIP transcription factors and chromatin acting as a nucleoskeleton cooperate to regulate nuclear membrane integrity. Full article

Curli fimbriae are a major component of biofilm formation in Escherichia coli, and their expression is regulated by numerous transcription factors and small regulatory RNAs (sRNAs). The RcsD-RcsC-RcsB phosphorelay system, which is involved in the envelope stress response, plays a role in this regulation. In this study, we report that DNase-I footprinting analysis revealed that the response regulator RcsB interacts with the −31 to +53 region of the promoter region of csgD, which encodes a major regulator of biofilm formation, and thus contributes to its transcriptional repression. Additionally, overexpression of RcsB or RcsB D56A that could not be phosphorylated by the histidine kinases RcsC and D both significantly reduced csgD expression and suppressed Curli formation. This indicates that the phosphorylation of RcsB has an insignificant impact on its affinity for its operator sites. Furthermore, we confirm that RcsB binds cooperatively to the csgD promoter region in the presence of the nucleoid-associated protein H-NS. Our study also confirms that RcsB positively regulates the expression of an sRNA, RprA, which is known to reduce mRNA csgD mRNA translation RprA via its binding to the 5′-untranslated region (UTR) of csgD. These findings indicate that, in E. coli, the RcsBCD system suppresses csgD expression through both direct transcriptional repression by the regulator RcsB and translational repression by the sRNA RprA. Full article

Bovine alphaherpesvirus 1 (BoHV-1) acute infection leads to latently infected sensory neurons in trigeminal ganglia. During lytic infection, the immediate early expression of infected cell protein 0 (bICP0) and bICP4 is regulated by an immediate early transcription unit 1 (IEtu1) promoter. A separate bICP0 early (E) promoter drives bICP0 as an early viral gene, presumably to sustain high levels during productive infection. Notably, bICP0 protein expression is detected before bICP4 during reactivation from latency, suggesting the bICP0 E promoter drives bICP0 protein expression during the early phases of reactivation from latency. The glucocorticoid receptor (GR) and Krüppel-like factor 4 (KLF4) cooperatively transactivate the bICP0 E promoter despite this promoter lacks a consensus GR response element (GRE). KLF and specificity protein (Sp) family members comprise a “super-family” of transcription factors. Consequently, we hypothesized Sp1 and Sp3 transactivated the bICP0 E promoter. These studies revealed GR and Sp3 or Sp1 cooperatively transactivated bICP0 E promoter activity. KLF4 and Sp3, but not Sp1, had an additive effect on bICP0 E promoter activity. Mutating the consensus Sp1 and CACCC binding sites proximal to the TATA box impaired promoter activity more than the Sp1 sites further upstream from the TATA box. Full article

Transcription factors (TFs) are the main regulators of eukaryotic gene expression. The cooperative binding of at least two TFs to genomic DNA is a major mechanism of transcription regulation. Massive analysis of the co-occurrence of overrepresented pairs of motifs for different target TFs studied in ChIP-seq experiments can clarify the mechanisms of TF cooperation. We categorized the target TFs from M. musculus ChIP-seq and A. thaliana ChIP-seq/DAP-seq experiments according to the structure of their DNA-binding domains (DBDs) into classes. We studied homotypic pairs of motifs, using the same recognition model for each motif. Asymmetric and symmetric pairs consist of motifs of remote and close recognition scores. We found that asymmetric pairs of motifs predominate for all TF classes. TFs from the murine/plant ‘Basic helix–loop–helix (bHLH)’, ‘Basic leucine zipper (bZIP)’, and ‘Tryptophan cluster’ classes and murine ‘p53 domain’ and ‘Rel homology region’ classes showed the highest enrichment of asymmetric homotypic pairs of motifs. Pioneer TFs, despite their DBD types, have a higher significance of asymmetry within homotypic pairs of motifs compared to other TFs. Asymmetry within homotypic CEs is a promising new feature decrypting the mechanisms of gene transcription regulation. Full article

The paralogues Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) control cell proliferation and cell fate determination from embryogenesis to ageing. In the skin epidermis, these proteins are involved in both homeostatic cell renewal and injury-induced regeneration and also drive carcinogenesis and other pathologies. YAP and TAZ are usually considered downstream of the Hippo pathway. However, they are the central integrating link for the signalling microenvironment since they are involved in the interplay with signalling cascades induced by growth factors, cytokines, and physical parameters of the extracellular matrix. In this review, we summarise the evidence on how YAP and TAZ are activated in epidermal keratinocytes; how YAP/TAZ-mediated signalling cooperates with other signalling molecules at the plasma membrane, cytoplasmic, and nuclear levels; and how YAP/TAZ ultimately controls transcription programmes, defining epidermal cell fate. Full article

Up to 40% of patients with diabetes mellitus will develop diabetic kidney disease (DKD), characterized pathologically by the accumulation of extracellular matrix proteins, which leads to the loss of kidney function over time. Our previous studies showed that the pan-protease inhibitor alpha 2-macroglobulin (A2M) is increased in DKD and is a critical regulator of the fibrotic response in glomerular mesangial cells (MC), an initial site of injury during DKD development. How A2M is regulated by high glucose (HG) has not yet been elucidated and is the focus of this investigation. Using serial deletions of the full A2M promoter, we identified the −405 bp region as HG-responsive in MC. Site-directed mutagenesis, siRNA, and ChIP studies showed that the transcription factor, nuclear factor of activated T cells 5 (NFAT5), regulated A2M promoter activity and protein expression in response to HG. Forkhead box P1 (FOXP1) served as a cooperative binding partner for NFAT5, required for A2M upregulation. Lastly, we showed that Smad3, known for its role in kidney fibrosis, regulated A2M promoter activity and protein production independently of HG. The importance of NFAT5, FOXP1, and Smad3 in A2M regulation was confirmed in ex vivo studies using isolated glomeruli. In conclusion, Smad3 is required for basal and HG-induced A2M expression, while NFAT5 and FOXP1 cooperatively regulate increased A2M transcription in response to HG. Inhibition of NFAT5/FOXP1 will be further evaluated as a potential therapeutic strategy to inhibit A2M production and attenuate profibrotic signaling in DKD. Full article

Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are important
sites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two  pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral  heterochromatin, remodel chromatin, and activate gene expression. Thus, we
predict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency. Full article

A robust predictive model was developed using 136 novel peroxisome proliferator-activated receptor delta (PPARδ) agonists, a distinct subtype of lipid-activated transcription factors of the nuclear receptor superfamily that regulate target genes by binding to characteristic sequences of DNA bases. The model employs various structural descriptors and docking calculations and provides predictions of the biological activity of PPARδ agonists, following the criteria of the Organization for Economic Co-operation and Development (OECD) for the development and validation of quantitative structure–activity relationship (QSAR) models. Specifically focused on small molecules, the model facilitates the identification of highly potent and selective PPARδ agonists and offers a read-across concept by providing the chemical neighbours of the compound under study. The model development process was conducted on Isalos Analytics Software (v. 0.1.17) which provides an intuitive environment for machine-learning applications. The final model was released as a user-friendly web tool and can be accessed through the Enalos Cloud platform’s graphical user interface (GUI). Full article

Currently, more than 55 million people around the world suffer from dementia, and Alzheimer’s Disease and Related Dementias (ADRD) accounts for nearly 60–70% of all those cases. The spread of Alzheimer’s Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD’s causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs’ ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs’ transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD. Full article

Characterization of gene regulatory mechanisms in cancer is a key task in cancer genomics. CCCTC-binding factor (CTCF), a DNA binding protein, exhibits specific binding patterns in the genome of cancer cells and has a non-canonical function to facilitate oncogenic transcription programs by cooperating with transcription factors bound at flanking distal regions. Identification of DNA sequence features from a broad genomic region that distinguish cancer-specific CTCF binding sites from regular CTCF binding sites can help find oncogenic transcription factors in a cancer type. However, the presence of long DNA sequences without localization information makes it difficult to perform conventional motif analysis. Here, we present DNAResDualNet (DARDN), a computational method that utilizes convolutional neural networks (CNNs) for predicting cancer-specific CTCF binding sites from long DNA sequences and employs DeepLIFT, a method for interpretability of deep learning models that explains the model’s output in terms of the contributions of its input features. The method is used for identifying DNA sequence features associated with cancer-specific CTCF binding. Evaluation on DNA sequences associated with CTCF binding sites in T-cell acute lymphoblastic leukemia (T-ALL) and other cancer types demonstrates DARDN’s ability in classifying DNA sequences surrounding cancer-specific CTCF binding from control constitutive CTCF binding and identifying sequence motifs for transcription factors potentially active in each specific cancer type. We identify potential oncogenic transcription factors in T-ALL, acute myeloid leukemia (AML), breast cancer (BRCA), colorectal cancer (CRC), lung adenocarcinoma (LUAD), and prostate cancer (PRAD). Our work demonstrates the power of advanced machine learning and feature discovery approach in finding biologically meaningful information from complex high-throughput sequencing data. Full article