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[Display omitted] Neuropathic pain is a highly prevalent and refractory condition, yet its mechanism remains poorly understood. While NR1, the essential subunit of NMDA receptors, has long been recognized for its pivotal role in nociceptive transmission, its involvement in presynaptic stimulation is incompletely elucidated. Transcription factors can regulate the expression of both pro-nociceptive and analgesic factors. Our study shows that transcription factor TFAP2A was up-regulated in the dorsal root ganglion (DRG) neurons, satellite glial cells (SGCs), and Schwann cells following spinal nerve ligation (SNL). Intrathecal injection of siRNA targeting Tfap2a immediately or 7 days after SNL effectively alleviated SNL-induced pain hypersensitivity and reduced Tfap2a expression levels. Bioinformatics analysis revealed that TFAP2A may regulate the expression of the Grin1 gene, which encodes NR1. Dual-luciferase reporter assays confirmed TFAP2A's positive regulation of Grin1 expression. Notably, both Tfap2a and Grin1 were expressed in the primary SGCs and upregulated by lipopolysaccharides. The expression of Grin1 was also down-regulated in the DRG following Tfap2a knockdown. Furthermore, intrathecal injection of siRNA targeting Grin1 immediately or 7 days post-SNL effectively alleviated SNL-induced mechanical allodynia and thermal hyperalgesia. Finally, intrathecal Tfap2a siRNA alleviated SNL-induced neuronal hypersensitivity, and incubation of primary SGCs with Tfap2a siRNA decreased NMDA-induced upregulation of proinflammatory cytokines. Collectively, our study reveals the role of TFAP2A- Grin1 in regulating neuropathic pain in peripheral glia, offering a new strategy for the development of novel analgesics. [ABSTRACT FROM AUTHOR]

[Display omitted] • MiR-1293 increases cisplatin-sensitivity in osteosarcoma. • MiR-1293 suppresses metastasis of osteosarcoma. • Higher levels of miR-1293 in prechemotherapy patients have better prognosis. • MiR-1293 targets TIMP1 to inactivate the Notch1/Hes1 and TGFBR1/Smad2/3 pathways. • Cisplatin elevated miR-1293 by hypomethylating its promoter and blocking TFAP2A. Chemotherapy is considered the primary treatment for osteosarcoma. however, its effectiveness is limited due to drug resistance and toxicity. Thus, identifying novel therapeutic targets to enhance the efficacy of chemotherapy is urgently needed. Here, we identified a novel cisplatin-sensitivity enhancing mechanism via up-regulation of the tumour suppressor gene, miR-1293. Meanwhile, higher levels of miR-1293 observed in prechemotherapy patients were associated with a more favorable prognosis. The mechanism underlying cisplatin upregulated miR-1293 expression involves hypomethylation of the miR-1293 promoter, which blocks the binding of the transcription repressor TFAP2A to the promoter. Furthermore, miR-1293 inhibits osteosarcoma progression by targeting TIMP1 to inactivate the Notch1/Hes1 and TGFBR1/Smad2/3 pathways, thereby promoting tumour cell death. The findings presented herein unveil a novel mechanism for enhancing cisplatin sensitivity and proposed a potential therapeutic strategy for osteosarcoma through pre-chemotherapy supplementation of miR-1293. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) yields a spectrum of phenotypic expression, leading to varying degrees of hypertension, maternal renal dysfunction and placental insufficiency with resultant maternal and neonatal morbidity. Increased sFLT1 expression contributing to angiogenic factor imbalance, placental hypoxia, failed immune adaptation to the fetus and defective decidualization are among the commonly proposed theories of PE pathogenesis. Recently researchers have focused their attention on the events that occur at the maternal fetal interface as potential contributors to PE pathogenesis. Decidual stromal cells (DSC) isolated from preeclamptic women show diminished ability to decidualize upon stimulation and reduced capacity to downregulate sFlt-1 levels. In this study, we sought to gain insight into the molecular mechanism(s) involved in the aberrant decidualization capacity of PE DSC. Our findings using qRT-PCR show that PE DSCs have 6-fold higher basal levels of transcription factor AP2A (TFAP2A) RNA compared to women without PE and that expression of TFAP2A increases during decidualization but only in DSCs of normotensive (NT) women. Silencing of TFAP2A using Trilencer siRNA upregulated sFLT1 expression only in NT-DSCs but suppressed the expression of decidualization markers PRL, IGFBP1 and their regulator FOXO1 in cells from both groups. Collectively, our observations suggest that TFAP2A acts as a repressor of sFLT1 and plays a necessary role in decidualization possibly through interacting with another factor that is aberrantly expressed in PE DSCs. [ABSTRACT FROM AUTHOR]

• 1.miR-205−5p is highly expressed in mouse thymic epithelial cells. • 2.miR-205−5p is steeply up-regulated from 1 to 9 months old TECs. • 3.miR-205−5p represses TECs proliferation via targeting Fa2h. • 4.Tfap2a can interact with miR-205−5p and be promoted by Fa2h. • 5.miR-205−5p regulates the age-associated thymus involution by mediating Fa2h-miR-205−5p-Tfap2a feedback regulatory circuit. Thymic epithelial cells (TECs) are essential regulators of T cell development and selection. microRNAs (miRNAs) play critical roles in regulating TECs proliferation during thymus involution. miR-205−5p is highly expressed in TECs and increases with age. However, the function and potential mechanism of miR-205−5p in TECs are not clear. miRNA expression was profiled using TECs from male and female mice at 1 and 3 months old. A total of 325 differentially expressed miRNAs (DEMs) were detected at different ages in two sexes. 24 of the DEMs had the same trend between males and females. Among them, miR-205−5p had the highest fold change. Our results showed that the expression of miR-205−5p was dramatically increased in TECs from 1 to 9 months old mice. miR-205−5p mimic inhibited TECs proliferation. Moreover, we confirmed that Fa2h was the direct target gene of miR-205−5p and FA2H was significantly decreased in TECs with increased expression of miR-205−5p. Silencing of Fa2h inhibited TECs proliferation. Furthermore, we found that the expression of Tfap2a could be promoted by FA2H and that TFAP2A could interact with miR-205−5p in TECs. Overall, miR-205−5p is an important regulator of TECs proliferation and regulates age-associated thymus involution via the miR-205−5p-FA2H-TFAP2A feedback regulatory circuit. miR-205−5p might act as a potential biomarker in TECs for age-related thymus involution. [ABSTRACT FROM AUTHOR]

• For the first time, NR4A1 transcript variants were identified in human granulosa cells (KGN cell line). • Two promoter regions at downstream of NR4A1 TSS were identified which is a vary rare phenomenon in gene transcription regulation. • For the first time, the view of ETS family involving in the pathological changes of PCOS characterized with hyperandrogen was proposed. Hyperandrogenism is one of the clinical and biochemical characteristics of polycystic ovary syndrome (PCOS). Our previous studies confirmed that nuclear receptor subfamily 4 group A member 1 (NR4A1), as a differentially expressed gene in the ovaries of PCOS patients, was upregulated by increased androgen. However, the potential mechanism of NR4A1 upregulation remains unknown. To elucidate the molecular mechanisms involved in NR4A1 regulation, we cloned and characterized the promoter regions of the NR4A1 gene using a series of truncated promoter plasmids in luciferase reporter assays. We identified two unique core promoters of NR4A1 located within the +1055/+1251 and +3183/+3233 regions relative to the transcription start site. TFAP2A downregulated NR4A1 expression, while five ETS transcription factors, ETS1, ELK1, ERG, FLI1 and SPI1, could upregulate NR4A1 promoter activity in HeLa cells. Of these transcription factors, ETS1 and ELK1 were the most effective ones. Moreover, all six transcription factors were confirmed to interact directly with the NR4A1 promoter. In conclusion, this study presents the first description that TFAP2A and ETS family signaling networks are involved in the androgen-mediated transcriptional regulation of NR4A1, which contributes to the understanding of the molecular mechanisms involved in the TFAP2A-NR4A1 and ETS-NR4A1 signaling networks in PCOS. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer in the world. High Mobility Group AT-Hook 1 (HMGA1) is found to be associated with the glycolytic pathway in a variety of cancers, and abnormal glycolysis function is one of the important characteristics of cancer cells. Therefore, this paper discusses the effect of HMGA1 on glycolysis of lung adenocarcinoma (LUAD) cells The mRNA expression data were downloaded from TCGA-LUAD database. Groups were set according to the median expression of HMGA1, followed by GSEA enrichment analysis. The upstream transcriptional regulators of HMGA1 were predicted by bioinformatics. The correlation between HMGA1 and Transcription Factor AP-2 Alpha (TFAP2A) and their expression in LUAD tissues were analyzed as well. mRNA expression levels of HMGA1 and TFAP2A were detected by qRT-PCR. The binding of HMGA1 and TFAP2A was demonstrated by ChIP and dual luciferase reporter assays. Cell function experiments were utilized to assay proliferation, apoptosis, glycolysis ability of LUAD cells, and glycolysis-related protein expression in each treatment group. HMGA1 was highly expressed in LUAD patients' tissues and enriched in the glycolytic pathway. Additionally, silencing HMGA1 markedly hampered cell proliferation and glycolysis, and promoted cell apoptosis. The upstream transcriptional regulator TFAP2A was predicted to be highly expressed in LUAD. ChIP and dual luciferase reporter assays confirmed the targeted relationship between HMGA1 and TFAP2A. Cell rescue assay confirmed that TFAP2A promoted glycolysis and LUAD progression by activating HMGA1. TFAP2A promotes glycolysis, proliferation and hampers apoptosis of LUAD cells by stimulating HMGA1. Hence, TFAP2A/HMGA1 may be a feasible therapeutic target for LUAD. All the data within this manuscript could be gotten from corresponding author at reasonable request. [ABSTRACT FROM AUTHOR]

Overexpression of TFAP2A has been linked to increased lymph node metastasis in basal-squamous bladder cancer. However, its downstream targets in bladder urothelial carcinoma (BLCA), the most malignant cancer of the urinary tract, remain unclear. In the current study, we aim to explore the function and mechanism of TFAP2A in BLCA. TFAP2A expression and the prognostic significance in BLCA was analyzed using TCGA and GTEX projects. TFAP2A was knocked-down in BLCA cells to study its impact on glucose uptake, lactate and ATP production, expression of HK2, and the number of vascular meshes formed by HUVEC. The target long noncoding RNAs (lncRNAs) of TFAP2A were predicted by bioinformatics tools, followed by ChIP-qPCR and luciferase assays. The downstream targets of TPRG1-AS1 were analyzed by microarray analysis. Rescue experiments were conducted for validation. TFAP2A upregulation in BLCA predicted dismal survival of patients. Loss of TFAP2A inhibited glycolysis (as evidenced by reduced glucose uptake, lactate, ATP production, and the expression of HK2) and angiogenesis (decreased number of vascular meshes formed by HUVEC). TFAP2A promoted the transcription of TPRG1-AS1. TPRG1-AS1 reversed the inhibitory effect of TFAP2A knockdown on glycolysis and angiogenesis in BLCA cells. TPRG1-AS1 inhibited the transcription of CRTAC1 by recruiting a DNA methyltransferase to the promoter of CRTAC1 and increasing the DNA methylation of its promoter. CRTAC1 inhibited glycolysis and angiogenesis in BLCA cells. TFAP2A silencing curbed tumor growth in vivo via the TPRG1-AS1/CRTAC1 axis. TFAP2A reduces CRTAC1 expression by promoting TPRG1-AS1 transcription, thereby expediting BLCA glycolysis and angiogenesis. • TFAP2A is highly expressed in BLCA and predicts poor prognosis for patients. • Depletion of TFAP2A inhibits glycolysis and angiogenesis in BLCA cells. • TFAP2A promotes TPRG1-AS1 transcription. • TPRG1-AS1 suppresses the expression of CRTAC1 through recruitment of DNMT3A. • TFAP2A affects BLCA tumor growth in vivo via the TPRG1-AS1/CRTAC1 axis. [ABSTRACT FROM AUTHOR]

Yamanaka factors are essential for establishing pluripotency in embryonic stem cells, but their function in multipotent stem cell populations is poorly understood. Here, we show that OCT4 and SOX2 cooperate with tissue-specific transcription factors to promote neural crest formation. By assessing avian and human neural crest cells at distinct developmental stages, we characterized the epigenomic changes that occur during their specification, migration, and early differentiation. This analysis determined that the OCT4-SOX2 dimer is required to establish a neural crest epigenomic signature that is lost upon cell fate commitment. The OCT4-SOX2 genomic targets in the neural crest differ from those of embryonic stem cells, indicating the dimer displays context-specific functions. Binding of OCT4-SOX2 to neural crest enhancers requires pioneer factor TFAP2A, which physically interacts with the dimer to modify its genomic targets. Our results demonstrate how Yamanaka factors are repurposed in multipotent cells to control chromatin organization and define their developmental potential. [Display omitted] • The OCT4-SOX2 dimer regulates the epigenomic landscape of neural crest (NC) cells • Dimer targets in the NC differ from those of embryonic stem cells • Pioneer factor TFAP2A interacts with OCT4-SOX2 to modify its genomic occupancy Utilizing genomic analysis to survey neural crest development, Hovland and Bhattacharya et al. identify Yamanaka factors OCT4 and SOX2 as key regulators of multipotency. The authors show how components of the pluripotency network cooperate with tissue-specific pioneer transcription factors to generate the neural crest stem cell state. [ABSTRACT FROM AUTHOR]

Abstract: Neuroblastoma, the most common extracranial solid tumour of childhood, is derived from neural crest progenitor cells. The TFAP2a transcription factor regulates neural crest patterning. We analysed TFAP2a protein expression in 97 primary neuroblastic tumors and report that TFAP2a was strongly expressed in poorly differentiated neuroblastomas. TFAP2a expression in tumor cells of differentiated neuroblastic tumors was below detection. TFAP2a was strongly expressed in 4 of 6 neuroblastoma cell lines tested, and TFAP2a siRNA mediated knock down in SH-EP cells reduced proliferation and induced a more differentiated phenotype associated with an increase in the expression of the differentiation marker neurotensin. [Copyright &y& Elsevier]

Patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) benefits from EGFR-tyrosine kinase inhibitor (TKI) treatment. However, drug resistance to EGFR-TKIs remains a great challenge. Single nucleotide polymorphisms (SNPs) may significantly influence prognosis of EGFR-TKI therapy. Herein, we hypothesized that the functional SNP in DACT2 , coding a pivotal inhibitor of the Wnt/β-catenin signaling, may affect gene expression, which in turn, impact prognosis of NSCLC treated with EGFR-TKIs. Genotypes of the DACT2 promoter rs9364433 SNP were determined in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The allele-specific regulation on DACT2 expression by rs9364433 and impacts of DACT2 on gefitinib sensitivity was evaluated in vitro and in vivo. Cox regression analyses demonstrated that rs9364433 was significantly associated with patient survival in both cohorts (all P < 0.05). Reporter gene assays and Electrophoretic Mobility Shift Assays demonstrated that rs9364433 has an allele-specific effect on gene expression modulated by transcription factor TFAP2A. The G allele associated with diminished TFAP2A binding leads to significantly decreased DACT2 expression in NSCLC cell lines and tissues. Consistently, DACT2 could evidently increase the anti-proliferation effect of gefitinib on NSCLC cells. Our findings elucidated potential clinical implications of DACT2, which may result in better understanding and outcome assessment of EGFR-TKI treatments. [ABSTRACT FROM AUTHOR]

In vitro gametogenesis is the process of making germline cells from human pluripotent stem cells. The foundation of this model is the quality of the first progenitors called primordial germ cells (PGCs), which in vivo are specified during the peri-implantation window of human development. Here, we show that human PGC (hPGC) specification begins at day 12 post-fertilization. Using single-cell RNA sequencing of hPGC-like cells (hPGCLCs) differentiated from pluripotent stem cells, we discovered that hPGCLC specification involves resetting pluripotency toward a transitional state with shared characteristics between naive and primed pluripotency, followed by differentiation into lineage-primed TFAP2A+ progenitors. Applying the germline trajectory to TFAP2C mutants reveals that TFAP2C functions in the TFAP2A+ progenitors upstream of PRDM1 to regulate the expression of SOX17. This serves to protect hPGCLCs from crossing the Weismann's barrier to adopt somatic cell fates and, therefore, is an essential mechanism for successfully initiating in vitro gametogenesis. • Human germline cell specification begins from a transitional pluripotent state • Human primordial germ cells are specified from lineage-primed progenitors • Lineage-primed TFAP2A progenitors have gastrulating and amnion cell identity • TFAP2C regulates SOX17 at the point of human primordial germ cell specification Using genetics, genomics, and single-cell RNA-seq, Chen et al. characterize the human germline trajectory, revealing two pluripotent cell transitions during primordial germ cell specification. They reveal the identity of primordial germ cell progenitors and show that TFAP2C prevents gastrulation and amnion-like fate at the point of primordial germ cell specification. [ABSTRACT FROM AUTHOR]