CLINICAL IMMUNOLOGY
·
2022
·
IF 10.19
Zewei Sun,Wenjing Chen,Zhen Wang,Shuai Wang,Jie Zan,Liangrong Zheng,Wenting Zhao
Atherosclerosis , characterized as the chronic inflammation of the arterial wall, is one of the leading causes of coronary artery disease (CAD), and macrophages are found to play essential roles in the initiation and progression of inflammation in atherosclerosis. N6-methyladenosine (m6A) modification, as the most abundant epi-transcriptomic modification in mRNA, is found to mediate the atherogenic inflammatory cascades in vascular endothelium . The detailed molecular mechanism of m 6 A methylation regulating inflammatory response during atherosclerosis is still not fully known. In this study, we find oxidized low-density lipoprotein (oxLDL) stimulation increases methyltransferases Mettl3 and Mettl14 expressions in macrophages, whereas the total m6A modification level in macrophages decreases under oxLDL stimulation. Matrin-3 (Matr3), an RNA binding protein , is identified to play a suppressive role on oxLDL-mediated macrophage inflammatory responses through inhibiting activation of pro-inflammatory signaling, mitogen-activated protein kinase (Mapk) by m6A-mediated mRNA decay via regulating the formation of Mettl3-Mettl14 complex. Moreover, we find that Matr3 expression decreases in the oxLDL-stimulated macrophages, and the peripheral blood-derived monocytes from patients with CAD, and overexpression of Matr3 significantly alleviates atherosclerosis development in vivo. Our study for the first time clarifies the role of Matr3 on macrophage inflammatory responses during atherosclerotic development, and supplies deep understanding on the relationship of m6A modification and inflammatory responses in atherosclerosis.
研究领域:
心血管疾病
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分子生物学
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炎症
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表观遗传学
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转录组学
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DOI
PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2026
·
IF 8.5
Juan Li,Lei Zhao,Mei Yang,Jingyu Hu,Haimin Li,Wei Yin,Yan Yan,Jinyan Gu,Jiyong Zhou
Pseudorabies virus (PRV) reprograms host inflammatory responses and epitranscriptomics, yet how these processes are connected remains unclear. Here, we report a JNK-WTAP-m⁶A-DUSP5 regulatory circuit that coordinates viral replication and inflammatory responses. PRV infection activated c-Jun N-terminal kinase (JNK), which phosphorylated wilms tumor-associated protein (WTAP) to drive its nuclear export and disrupt the activity of the m⁶A methyltransferase complex. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and biochemical analyses revealed a global reduction of N6-methyladenosine (m⁶A) on host transcripts, particularly on proinflammatory cytokines, alongside widespread m⁶A modification sites on viral transcripts. Consequently, reduced m⁶A prolonged the half-lives of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) mRNAs, as well as viral transcripts, thereby synergistically promoting PRV replication. Inhibition of JNK activity or restoration of m⁶A modification suppressed PRV replication in vitro and in vivo . Moreover, the m⁶A hypomethylation stabilized dual-specificity phosphatase 5 (DUSP5) transcripts at early infection, transiently restraining JNK activation and forming a negative feedback loop. These findings demonstrate that PRV reprograms the m⁶A machinery via JNK-mediated WTAP phosphorylation and highlights RNA methylation restoration as a promising antiviral strategy.
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Fubin Zhu,Hongzhi Li,Xiang Li,Chunxiu Du,Ting Wang,Xuling Zhou,Xiaobei Xie,Yunxia Shao,Yingzhi Huang,Yanling Hu,Xinxin Guo,Bin Zhu,Shanshan Yu,Xiaoyan Zhang,Binghai Zhao
Focal segmental glomerulosclerosis (FSGS) is a common glomerular lesion that manifests as a primary podocyte injury. Multiple genetic risk factors have been reported to be associated with the development of FSGS. However, whether epigenetic factors, especially N6-methyladenosine (m6A) modifications, are involved in the pathogenesis of FSGS remains unclear. By generating a mouse line with a specific deletion of N6-adenosine-methyltransferase-like 3 ( Mettl3 ) in podocytes ( Mettl3 podko mice), podocytes are isolated and performed RNA-seq. It is shown that RNA m6A methylation levels are reduced in the renal glomeruli of both animal models and patients with FSGS. A significant decrease in RNA m6A levels in podocytes and the development of an FSGS phenotype are observed in the Mettl3 podko mice. Furthermore, RNA-seq and m6A-immunoprecipitated RNA sequencing revealed that silencing Mettl3 expression in podocytes led to a gene expression profile associated with slit diaphragm dysfunction. RNA immunoprecipitation assay and hybridization chain reaction (HCR) analysis further identified the slit diaphragm marker TJP1 as a potential target of Mettl3. Moreover, loss- and gain-of-function analyses showed that Mettl3 enhances podocyte RNA m6A modification, probably through the TJP1–CDC42 pathway. Finally, treatment of Mettl3 podko and adriamycin (ADR)-induced FSGS mice with m6A-mimic compounds markedly ameliorated the progression of FSGS. The findings demonstrate that Mettl3 -mediated RNA m6A modification is essential for maintaining podocyte architecture and function and represents a potential therapeutic target for FSGS.
研究领域:
肾病学
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表观遗传学
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分子生物学
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RNA生物学
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DOI
PubMed
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 35
·25561-25570
·
IF 3.9
Chen Chen,Mei Zhao,Jingyi Guo,Xia Kuang,Zilin Chen,Fang Wang
N6-Methyladenosine (m6A) is a prevalent modification in eukaryotic mRNAs and is linked to various human cancers. The fat mass and obesity-associated protein (FTO), a key m6A demethylase, is crucial in m6A regulation, affecting many biological processes and diseases. Detecting FTO is vital for clinical and research applications. Our study leverages the specific cleavage properties of the MazF endoribonuclease to design an electrochemical method with signal amplification guided by streptavidin-horseradish peroxidase (SA-HRP), intended for FTO detection. Initially, the compound N3-kethoxal is employed for its reversible tagging ability, selectively attaching to guanine (G) bases. Subsequently, dibenzocyclooctyne polyethylene glycol biotin (DBCO-PEG4-Biotin), is introduced through a reaction with N3-kethoxal. HRP is then employed to catalyze the redox system to enhance the current response further. A promising linear correlation between the peak current and the FTO concentration was observed within the range of 7.90 × 10−8 to 3.50 × 10−7 M, with a detection limit of 5.80 × 10−8 M. Moreover, this method assessed the FTO inhibitor FB23's inhibitory effect, revealing a final IC50 value of 54.73 nM. This result aligns with the IC50 value of 60 nM obtained through alternative methods and is very close to the values reported in the literature. The study provides reference value for research into obesity, diabetes, cancer, and other FTO-related diseases, as well as for the screening of potential therapeutic drugs.
研究领域:
分子生物学
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医学检验
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癌症研究
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Dong Liu,Meihua Shan,Rong Zeng,Meng He,Xufang Dai,Lu Lu,Mingzhen Yang,Haiyan He,Yang Zhang,Li Xiang,An Chen,Liangbo Sun,Fengtian He,Jiqin Lian
N6-methyladenosine (m6A) serves as the most abundant posttranscription modification. However, the role of m6A in tumorigenesis and chemotherapeutic drugs sensitivity remains largely unclear. Present research focuses on the potential function of the m6A writer KIAA1429 in tumor development and sorafenib sensitivity in liver cancer. We found that the level of KIAA1429 was significantly elevated in liver cancer tissues and cells and was closely associated with poorer prognosis. Functionally, KIAA1429 promoted the proliferation and Warburg effect of liver cancer cells in vitro and in vivo . RNA-seq and MeRIP-seq analysis revealed the glycolysis was one of the most affected pathways by KIAA1429, and m6A-modified HK1 was the most likely targeted gene to regulate the Warburg effect. KIAA1429 depletion decreased Warburg effect and increased sorafenib sensitivity in liver cancer. Mechanistically, KIAA1429 could affect the m6A level of HK1 mRNA through directly binding with it. Moreover, KIAA1429 cooperated with the m6A reader HuR to enhance HK1 mRNA stability, thereby upregulating its expression. These findings demonstrated that KIAA1429/HK1 axis decreases the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect, which may provide a novel therapeutic target for liver cancer treatment
研究领域:
肿瘤学
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分子生物学
·
癌症治疗
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DOI
PubMed
高影响因子
Gut Microbes
·
2025
·
IF 11
Tong Jin,Si-Yuan Li,Hong-Li Zheng,Xiao-Dan Liu,Yue Huang,Gan Ma,Ya-Xuan Zhao,Xiao-Tian Zhao,Li Yang,Qi-Hui Wang,Hong-Jun Wang,Chengyong Gu,Zhiqiang Pan,Fuqing Lin
The gut microbiota has been linked to a number of neurological disorders. However, it is unclear whether the gut microbiota is involved in the genesis of chronic itch, a refractory condition that afflicts patients both physically and mentally. Here, we report that depletion of gut microbiota enhances tolerance to itch in mice orally administered with antibiotics (ABX) and mice free of germ. Of note, oral gavage with Bacteroides fragilis (B. fragilis), a prominent species of the genus Bacteroides with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or B. fragilis depletion caused a decrease in RNA N6-methyladenosine (m6A) demethylase FTO expression in the dorsal horn and a consequent increase in RNA m6A sites in Mas-related G protein-coupled receptor F (MrgprF) mRNA, leading to decreased MRGPRF protein. The downregulation of FTO was triggered by inactivation of ETS proto-oncogene 1 (ETS1), a transcription factor that binds to the Fto promoter. These findings support a gut microbe – spinal connection in modulation of itch sensation in RNA m6A epigenetic-dependent manner and highlight a critical role of ALC in linking the altered B. fragilis and itch dysfunction.
研究领域:
神经科学
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微生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Neurobiology of Stress
·
2021
·
IF 5.441
Peng-Fei Wu,Qian-Qian Han,Fu-Feng Chen,Tian-Tian Shen,Yi-Heng Li,Yu Cao,Jian-Guo Chen,Fang Wang
Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N 6 -methyladenosine (m 6 A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m 6 A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m 6 A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m 6 A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m 6 A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.
研究领域:
神经科学
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药理学
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表观遗传学
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DOI
PubMed
高影响因子
Molecular Biomedicine
·
2026
·Vol. 7
·期 1
·62
·
IF 13
Ma Hehua,Hong Yuxin,Xu Zhi,Weng Zuyi,Yang Yuanxun,Song Wei,Li Juan
N 6 -methyladenosine (m 6 A) modifications play a vital role in hepatocellular carcinoma (HCC) progression. However, the function of m 6 A reader proteins in HCC remains poorly understood. Here, we elucidate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in HCC. In here, we analyzed IGF2BP2 expression in HCC using bioinformatics and clinical samples. The functional role of the IGF2BP2-RELB regulatory axis in HCC progression was assessed through cytological assays and a xenograft HCC mouse model. RNA sequencing, Western blotting, Actinomycin-D assays, and RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) assays were performed to investigate the regulatory mechanisms of IGF2BP2 on RELB expression. We found high expression of IGF2BP2 in HCC was positively correlated with poor prognosis. Gain- and loss-of-function assays demonstrated that IGF2BP2 was essential for HCC cell proliferation and migration. IGF2BP2 directly bound to RELB mRNA and enhanced its stability via the KH3/4 domain. Upregulated RELB promoted nuclear translocation of the RELB:p52 dimer, leading to activation of the NF-κB signaling pathway. Furthermore, inhibition of IGF2BP2 and RELB suppressed HCC tumor progression both in vitro and in vivo. Our study demonstrates that IGF2BP2 plays a critical role in HCC progression by stabilizing RELB mRNA and activating the NF-κB signaling pathway. The results suggest that IGF2BP2 may be a potential therapeutic strategy for HCC.
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Dongkai Jia,Lulu Liu,Wei Liu,Mengrou Geng,Jinjie Li,Haoqiang Guo,Ke Xu,Pinyi Liu,Ying Xin
Cuproptosis is a recently identified form of regulated cell death triggered by intracellular copper (Cu) overload. Diabetic conditions are characterized by disrupted Cu homeostasis. This study reveals a critical mechanistic link between the RNA methyltransferase WTAP and hypoxia-inducible factor-2α (HIF-2α) in promoting cardiomyocyte cuproptosis in diabetic cardiomyopathy (DCM). In both diabetic mouse hearts and high-fat/high-glucose plus Cu chloride-treated AC16 cardiomyocytes, elevated levels of WTAP and HIF-2α were observed alongside increased cuproptosis. Mechanistically, WTAP facilitates m 6 A-dependent upregulation of HIF-2α, which transcriptionally activates the divalent metal transporter 1 (DMT1). Enhanced DMT1 expression leads to intracellular Cu accumulation, subsequently inducing cuproptosis and driving DCM progression. Importantly, the clinically used agent dexmedetomidine (DEX) was found to alleviate DCM in vivo, at least in part, by suppressing DMT1 expression and thereby inhibiting cuproptosis. These findings identify the WTAP/HIF-2α/DMT1 axis as a key regulator of Cu overload and cuproptosis in DCM, highlighting its therapeutic potential.
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
·
表观转录组学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Yubin Long,Yuan Ma,Houzhi Yang,Xiangbin Wang,Jigeng Fan,Yong Li,Bo Tao,Tianwei Sun
Promoting osteogenic differentiation and inhibiting osteoclast formation remain significant challenges in the treatment of osteoporosis. With the growing understanding of osteoporosis, increasing literature has highlighted the regulatory role of m6A methylation in this condition. However, there is currently no reliable method to stably regulate cellular m6A methylation levels. Here, we report a novel approach utilizing alendronate (aln)-modified mesoporous silica nanoparticles (MSNs) to deliver sodium bicarbonate and piR7472, modulating cellular behavior. Our experimental results demonstrate that Aln modification enables the nanoparticles to stably target hydroxyapatite, thereby accumulating in osteoporotic regions. Sodium bicarbonate suppresses osteoclastogenesis, while piR7472 enhances m6A methylation, promoting osteogenic differentiation of bone marrow stromal cells (BMSCs). Computed tomography (CT) and hematoxylin and eosin (HE) staining showed that after 2 weeks of treatment with MSNs-Na@piR7472, cortical bone thickened, trabecular bone density increased, collagen fiber thickness improved, and both the number and staining area of osteoclasts were significantly reduced. These findings indicate a marked improvement in osteoporosis.
研究领域:
医学
·
分子生物学
·
纳米医学
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DOI
高影响因子
Cell Reports
·
2020
·
IF 8.109
Bowen Rong,Qian Zhang,Jinkai Wan,Shenghui Xing,Ruofei Dai,Yuan Li,Jiabin Cai,Jiaying Xie,Yang Song,Jiawei Chen,Lei Zhang,Guoquan Yan,Wen Zhang,Hai Gao,Jing-Dong J. Han,Qianhui Qu,Honghui Ma,Ye Tian,Fei Lan
Summary N6 methylation at adenosine 1832 (m 6 A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m 6 A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.
研究领域:
分子生物学
·
癌症研究
·
细胞生物学
·
遗传学
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DOI
PubMed
高影响因子
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