关键词： TRANSLATION   MICRORNAS   PROLIFERATION   METASTASIS  

摘要： 7-methylguanosine (m(7)G) modification is recently found to conservatively exist in RNA internal position besides mRNA caps and mediates the various RNA metabolisms. As the core confirmed transmethylase of m(7)G modification, METTL1 has been reported in certain human cancers. However, the role of internal m(7)G at miRNAs and its core writer METTL1 in bladder cancer (BCa) remains to be elucidated. Here, we demonstrated that METTL1 was indispensable for BCa proliferation and metastasis in vitro and in vivo. By combining miRNA sequencing, m(7)G methylated RNA immunoprecipitation (MeRIP) and RIP, we identified METTL1 promoted the processing of miR-760 in an m(7)G-dependent manner. Transcription sequencing suggested that METTL1 indirectly degrades tumor suppressor ATF3 mRNA mediated by miR-760. Together, we concluded a regulatory axis composed of METTL1/m(7)G/miR-760/ATF3 in regulating BCa progression and provided potential therapeutic targets for BCa.

关键词： IMMUNOGENIC CELL-DEATH   DENDRITIC CELLS   ADAPTIVE-RESPONSE   ATF3   TRAFFICKING   MACROPHAGES   MATURATION   IMMUNITY   EVASION   INNATE  

摘要： Dendritic cells (DC) present tumour antigens to T cells but this process is defective in the tumour microenvironment. Here the authors find that downregulation of cholesterol 25-hydroxylase underlies defective cross presentation of tumour antigens. Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8(+) T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.

关键词： Glucose starvation   ptau(S409)   PKAc alpha   ATF3   PROTEIN-KINASE-A   TAU-PROTEIN   PHOSPHORYLATION   BRAIN   HYPERPHOSPHORYLATION   CAMP   INVOLVEMENT   DEPRIVATION   INHIBITION   EXPRESSION  

摘要： In this work, we report that glucose starvation (GS) causes ptau(S409) increase, which may participate in GS-induced neurites retraction in neuro-2a (N2a) cells. Upon GS treatment, PKAc alpha was stimulated at mRNA and protein levels. Luciferase reporter gene assays indicated that GS regulated PKAc alpha expression through a core promoter (-345 to -95 bp upstream the transcription starting site) consisting of a cis-acting element of Activating Transcription Factor 3 (ATF3). Knockdown and over-expression experiments demonstrate that ATF3 transcriptionally regulated PKAc alpha expression. Moreover, GS stimulated ATF3 expression in a time-dependent manner. These findings reveal that glucose starvation induces ptau(S409) increase in N2a cells through an ATF3- PKAc alpha axis, which shed some light on the relationship between brain glucose metabolism and neurodegenerative diseases.

关键词： ATF3   Atherosclerosis   Angiogenesis   Inflammation   Endothelial cell plasticity   ACTIVATING TRANSCRIPTION   GENE-EXPRESSION   MESENCHYMAL TRANSITION   ENDOTHELIAL-CELLS   INDUCED APOPTOSIS   NITRIC-OXIDE   RECEPTOR 1   MACROPHAGES   INDUCTION   CHOLESTEROL  

摘要： Atherosclerosis, the pathophysiological basis of most malignant cardiovascular diseases, remains a global concern. Transcription factors play a key role in regulating cell function and disease progression in developmental signaling pathways involved in atherosclerosis. Activated transcription factor (ATF) 3 is an adaptive response gene in the ATF/cAMP response element binding (CREB) protein family that acts as a transcription suppressor or activator by forming homodimers or heterodimers with other ATF/CREB members. Appropriate ATF3 expression is vital for normal physiological cell function. Notably, ATF3 exhibits distinct roles in vascular endothelial cells, macrophages, and the liver, which will also be described in detail. This review provides a new perspective for atherosclerosis therapy by summarizing the mechanism of ATF3 in atherosclerosis, as well as the structure and pathophysiological properties of ATF3. Key messages center dot In endothelial cells, ATF3 overexpression aggravates oxidative stress and inflammation. center dot In macrophages and liver cells, ATF3 can act as a negative regulator of inflammation and promote cholesterol metabolism. center dot ATF3 can be used as a potential therapeutic factor in the treatment of atherosclerosis.

关键词： Chronic stress   Interferon signaling   Microglia   Transcriptome   Chromatin accessibility   Activating transcription factor 3   DEPRESSIVE-LIKE BEHAVIOR   NECROSIS-FACTOR-ALPHA   PSYCHOLOGICAL STRESS   PREFRONTAL CORTEX   MAJOR DEPRESSION   LIFE EVENTS   BRAIN   ATF3   ACTIVATION   EXPRESSION  

摘要： Stress-induced neuroinflammation is considered an important mechanism in the pathogenesis of depression. As immune effector cells in the brain, microglia play an essential role in neuroinflammation under stress, but the underlying mechanism remains controversial. Here, we performed RNA-seq and ATAC-seq to study microglia-specific epigenomic changes in mice after 12 weeks of exposure to mild stress. Our study revealed that chronic stress induced pronounced anxiety and depressive-like behavioral changes. However, microglia did not manifest a state of neuroinflammatory activation; instead, they displayed morphological changes characterized by hyper-ramification. Furthermore, we revealed large-scale transcriptional repression in microglia isolated from the stressed brain, including many interferon (IFN)-regulated genes (IRGs) and some encompassing DNA repeats. GSEA showed that the down-regulated genes were enriched in the IFN-mediated neuroimmune signaling path-ways. In addition, integrative analysis with a published scRNA-seq dataset revealed that these down-regulated genes were enriched in a distinct subpopulation of "Interferon microglia". ATAC-seq analysis further showed that differential gene expression was positively correlated with the changes in chromatin accessibility, and the IFN-stimulated response element (ISRE) was enriched in the down-regulated ATAC-seq loci. Interestingly, this phenotype was not associated with the production of IFNs. Instead, the gene encoding Activating Transcription Factor 3 (ATF3) was significantly increased in the stressed microglia, which might contribute to the transcrip-tional repression of IRGs. Our study reported microglia-specific transcriptional repression of IRGs independent of the production of IFNs, providing some new insights into neuroimmune dysregulation under prolonged stress.

关键词： Osteoarthritis (OA)   Metabolism-related genes   Transcription factors (TFs)   Pathways   Small molecules   ARTICULAR-CARTILAGE   OSTEOARTHRITIS   ATF3   EXPRESSION   PATHOGENESIS   HIP   CHONDROCYTES   INFLAMMATION   GLYCOLYSIS   SIGNATURES  

摘要： Metabolic alteration of articular cartilage is associated with the pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors (TFs), and relevant pathways. Overall, RNA sequencing profiles of articular cartilage were collected from the GEO database. Metabolism -related genes and OA-related hallmarks were collected from the MSigDB v7.1. Differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Gene Set Variation Analysis (GSVA) were conducted to identify pathways or hallmarks that were related to the patho-genesis of OA. The Pearson correlation analysis was used to establish the regulatory network among transcription factors, metabolism-related genes, and hallmarks. To further confirm the regulation of the identified transcrip-tion factors, Chromatin Immunoprecipitation-sequencing (ChIP-seq) was conducted, and single-cell sequencing was used to locate the cell clusters. Connectivity Map (CM) analysis were also conducted to identify the potential specific bioactive small molecules targeting the metabolic alteration of osteoarthritis. scTPA database was used to detect activated signaling pathways. Collectively, a total of 74 and 38 differentially expressed metabolism -related genes and TFs were retrieved. Skeletal system development, extracellular matrix, and cell adhesion molecule binding were important pathways in GO analysis. Human papillomavirus infection, PI3K-Akt signaling pathway, and Human T-cell leukemia virus 1 infection were the top 3 pathways in KEGG. 7 and 12 hallmarks were down-and up-regulated in GSVA, respectively. Ten bioactive small molecules may be potential treatments of OA by regulating the metabolism of articular cartilage. ChIP-seq analysis showed high relativity between transcription factors and their target genes. Furthermore, single-cell sequencing confirms the high expression of identified transcription f

关键词： CYSTINE/GLUTAMATE ANTIPORTER   SYSTEM   MECHANISMS   ROLES   ROS  

摘要： Purpose. Osteoporosis is a complication of type 2 diabetes, and it is characterized by reduced bone mass, augmented bone fragility, and increased risk of fracture, thus reducing patient quality of life, especially in the elderly. Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), but the specific underlying mechanisms remain largely unknown. This study clarified the role of activating transcription factor 3 (ATF3) in T2DOP and explored its specific regulatory mechanism, providing a new treatment target for T2DOP. Methods. We cultured hFob1.19 cells in high glucose (HG, 35 mM) and knocked down ATF3 using short hairpin RNA (shRNA). We then measured cell viability, assessed morphology, quantified the expression of ATF3 and glutathione peroxidase 4 (GPX4), detected the levels of reactive oxygen species (ROS) and lipid peroxides, and determined the osteogenic function of osteoblasts. Cystine/glutamate antiporter (system Xc(-)) activity was evaluated by determining the expression of SLC7A11 and the levels of glutathione (GSH) and extracellular glutamate. We constructed a T2DOP rat model and observed the effect of ATF3 on ferroptosis and T2DOP by knocking down ATF3 using small interfering RNA (siRNA). Then, we evaluated the levels of iron metabolism, lipid peroxidation, and bone turnover in serum, detected the expression of ATF3, SLC7A11, and GPX4 in bone tissues, and assessed bone microstructure using microcomputed tomography. Results. ATF3 expression was increased in osteoblasts under HG condition and in T2DOP rats. Inhibiting the function of ATF3 increased GPX4 levels and reduced the accumulation of ROS and lipid peroxides. These changes inhibited the ferroptosis of osteoblasts and improved osteogenic function. In addition, HG induced ATF3 upregulation, resulting in decreased SLC7A11 expression and lower levels of intracellular GSH and extracellular glutamate. Conclusion. Osteoblast ferroptosis under HG conditions is ind

关键词： Data reanalysis   Data mining   JEV   Japanese   Encephalitis   miRNA   DEG   ATF3   MYH10   PAQR8   Innate   Antiviral   Microarray   RNA-Seq   INHIBITS PROLIFERATION   CANCER   RECOGNITION   INDUCTION   CELLS  

摘要： Purpose: Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV), is the principal cause of viral encephalitis in South-East Asian and Western Pacific countries; accounting for 68,000 cases, and up to 20,400 fatalities, annually across the world. Despite being a high-risk condition, there is no specific treatment for JE. Given rapid additions in genomics databases and the power of data reanalysis in addressing critical medical questions, the present study was designed to identify novel host factors that might have potential roles in JEV ***: We extracted microarray and RNA-Seq data sets from NCBI-GEO and compared mock and JEV-infected samples. Raw data from all the studies were re-analyzed to identify host factors associated with JEV ***: We identified several coding and non-coding host factors that had no prior known role in viral infections. Of these, the coding transcripts: Myosin Heavy Chain 10 (MYH10), Progestin and AdipoQ Receptor Family Member 8 (PAQR8), and the microRNAs: hsa-miR-193b-5p, hsa-miR-3714 and hsa-miR-513a-5p were found to be novel host factors deregulated during JEV infection. MYH10 encodes a conventional non-muscle myosin, and mutations in MYH10 have been shown to cause neurological defects. PAQR8 has been associated with epilepsy, which exhibits symptoms similar to JEV infection. JE is a neuro-degenerative disease, and the known involvement of MYH10 and PAQR8 in neurological disorders strongly indicates potential roles of these host factors in JEV infection. Additionally, we observed that MYH10 and PAQR8 had a significant negative correlation with Activating transcription factor 3 (ATF3), which is a previously validated modulator of JEV infection. ATF3 is a transcription factor that binds to the promotors of genes encoding other transcription factors or interferonstimulated genes and negatively regulates host antiviral responses during ***: Our findings demonstrate the significance of

关键词： ATF3   glucolipid metabolism   metabolic organ   metabolic diseases  

摘要： Lipids and glucose exert many essential physiological functions,such as providing raw materials or energy for cellular biosynthesis,regulating cell signal transduction,and maintaining a constant body *** of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases,such as obesity,diabetes,and cardiovascular ***,intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic *** transcription factor 3(ATF3)is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation,apoptosis,DNA repair,and *** evidence has illustrated the vital roles of ATF3 in glucolipid ***3 inhibits intestinal lipid absorption,enhances hepatic triglyceride hydrolysis and fatty acid oxidation,promotes macrophage reverse cholesterol transport,and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and *** addition to its role in lipid metabolism,ATF3 has also been identified as an important regulator of glucose ***,we summarize the recent advances in the understanding of ATF3,mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.