INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Feng Chen,Mingyi Zhou,Wei Chen,Wenjing Geng,Liang Lu,Guanwang Shen,Ping Lin,Qingyou Xia,Ping Zhao,Zhiqing Li
N6-methyladenosine (m6A) is the most prevalent internal modification on mRNA and plays critical roles in various biological processes including virus infection. It has been shown that m6A methylation is able to regulate virus proliferation and host innate immunity in mammals and plants, however, this antiviral defense in insects is largely unknown. Here we investigated function of m6A and its associated methyltransferases in nucleopolyhedrovirus (BmNPV) infection in silkworm. We reported significant changes of m6A methyltransferases METTL3 and METTL14 upon BmNPV treatment. Knockdown of METTL3 and METTL14 enhanced BmNPV infection and promoted viral proliferation, whereas overexpression of these enzymes could prevent viral replication. Further study revealed that host heat shock cognate 70 ( Hsc70 ) as a target gene of m6A would contribute to BmNPV proliferation. CRISPR-dCas9-targeted methylation of Hsc70 by METTL3/METTL14 decreased its expression and further attenuated BmNPV infection. Consistently, knockout of METTL3 in silkworm individuals by CRISPR-Cas9 reduced overall m6A levels, which led to rapid death of silkworms and increase of BmNPV upon virus infection likely due to upregulated expression of Hsc70 . Collectively, these findings provided a novel insight into antiviral activity of m6A and demonstrated a distinct immune response via attenuating host Hsc70 expression to counteract BmNPV replication in lepidopteran silkworm.
CAS / MDL:
研究领域:
昆虫学
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分子生物学
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病毒学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2024
·Vol. 81
·期 1
·1-16
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IF 6.2
Zhao Yongzhao,Chen Longting,Xiang Qian,Lin Jialiang,Jiang Shuai,Li Weishi
Background The ligamentum flavum (LF) is an important anatomical structure of the spine. Ossification of the LF (OLF) has become the leading cause of thoracic spinal stenosis. Circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification are reported to be associated with several human diseases. However, the role of circRNAs and m6A modification in the pathogenesis of OLF has not been fully investigated. Here, we aimed to explore the vital function of circRNAs and m6A modification in OLF. Materials and methods We analysed the circRNA expression of 4 OLF tissues and 4 normal LF tissues using bioinformatic analysis and identified circCDK14 for further analysis. We investigated the effects of circCDK14 on the osteogenic differentiation of LF cells. We observed that circCDK14 regulated its target genes by binding to miRNAs as a miRNA sponge. Moreover, the circRNA pull-down assay indicated that RNA-binding proteins might regulate the expression of circCDK14 via m6A modification. Results CircCDK14 was significantly upregulated in OLF tissues compared to normal LF tissues. Overexpression of circCDK14 promoted the osteogenic differentiation of LF cells. Mechanistically, CircCDK14 promoted the expression of ALF transcription elongation Factor 4 (AFF4) by serving as a sponge for miR-93-5p. Moreover, Wilms tumour 1-associated protein (WTAP) increased the stability of circCDK14 via N6-methyladenosine modification. Conclusion The m6A-modified CircCDK14 binding to miR-93-5p played an important role in the osteogenesis of LF cells by targeting AFF4, providing a promising therapeutic target for OLF.
研究领域:
分子生物学
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表观遗传学
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骨科
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生物信息学
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DOI
PubMed
高影响因子
CHEMOSPHERE
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2023
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IF 8.8
Lin Han,Jingyu Wang,Lei Zhang,Jiaru Jing,Wei Zhang,Ziyan Liu,Ai Gao
Benzene is a universal ambient pollutant. Population-based studies have shown that benzene exposure affects male fertility. However, the mechanism of benzene-induced reproductive toxicity is unknown. Here, we established a dynamic inhalation model and exposed C57BL/6J mice to 0, 10, and 50 ppm benzene (6 h/day, 6 days/week, 7 weeks). Our study revealed that benzene exposure caused testicular injury, including structural damage to spermatogenic tubules, reduced semen quality, and decreased testosterone levels. In addition, the decrease in the global level of N 6 -Methyladenosine (m 6 A) and the change of m 6 A important regulatory enzymes in mice testes suggested that m 6 A was involved in the benzene-induced testicular injury. Further genome-wide m 6 A methylation analysis showed that 1469 differential m 6 A peaks were present in the testes of control and benzene groups, indicating that benzene exposure modulated m 6 A methylation in testes. Furthermore, the comprehensive analysis of m 6 A-sequencing and transcriptome revealed that hypermethylated Rara and its consequent reduced expression impaired the sperm production process. In particular, melatonin alleviated benzene-induced testicular injury by modulating m 6 A-related genes. Overall, our research provides a new idea and fundamental knowledge into the possible mechanisms of m 6 A modifications in benzene-induced testicular impairment, as well as a new experimental basis for benzene-induced male fertility therapy.
研究领域:
毒理学
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生殖生物学
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表观遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Biyun Chen,Lujiao Wang,Luyao Li,Mei Zhou,Shuya Pan,Qin Wang,Yaxuan Hou,Xue Zhou
Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N 6 -methyladenosine (m 6 A) modification is known to modulate pri-miRNA processing. However, whether m 6 A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m 6 A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m 6 A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m 6 A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m 6 A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What’s more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m 6 A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.
研究领域:
癌症生物学
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分子生物学
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毒理学
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表观遗传学
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DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
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2019
·Vol. 42
·期 16
·2668-2678
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IF 2.516
Ruijuan Liu,Fang Zhao,Jingyao Wei,Pei Yu,Ji Zhang,Yueqin Wang,Zeyun Li,Jiali Zhang,Xiaojian Zhang,Xin Tian
Ribonucleic acid N 6 -methyladenosine methylation plays an important role in a variety of biological processes and diseases. Acetaminophen-induced hepatotoxicity is one of the major challenges faced by clinicians. To date, the link between N 6 -methyladenosine and acetaminophen-induced hepatotoxicity has not been studied. In this study, a simple ultra high performance liquid chromatography with tandem mass spectrometry method was developed for the simultaneous determination of five nucleosides (adenosine, uridine, cytidine, guanosine, and N 6 -methyladenosine) in messenger ribonucleic acid. After enzymatic digestion of messenger ribonucleic acid, the nucleosides sample was separated on an Acquity UPLC column with gradient elution using methanol and 0.02% formic acid water, and detected by a Qtrap 4500 mass spectrometer with an electrospray ionization mode. The method was validated over the concentration ranges of 4–800 ng/mL for adenosine, uridine, cytidine, and guanosine and 0.1–20 ng/mL for N 6 -methyladenosine. It was successfully applied to the determination of N 6 -methyladenosine levels in liver messenger ribonucleic acid in an acetaminophen-induced hepatotoxicity mouse model and a control group. This study offers a method for the determination of nucleoside contents in epigenetic studies and constitutes the first step toward the investigation of ribonucleic acid methylation in acetaminophen-induced hepatotoxicity, which will facilitate the elucidation of its mechanism.
研究领域:
分析化学
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毒理学
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表观遗传学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Lixiao Zhou,Renjie Li,Fu Wang,Ruiqi Zhou,Yinyin Xia,Xuejun Jiang,Shuqun Cheng,Fanghong Wang,Danyang Li,Jun Zhang,Lejiao Mao,Xuemei Cai,Hongyang Zhang,Jingfu Qiu,Xin Tian,Zhen Zou,Chengzhi Chen
Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m 6 A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m 6 A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.
研究领域:
神经科学
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毒理学
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分子生物学
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代谢组学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-15
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IF 9.6
Cen Junjie,Zhao Dongliang,Shi Xin,Chen Jinlong,Zhou Hang,Liang Yanping,Gui Chengpeng,Chen Wei,Luo Junhang,Chen Xu
Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
研究领域:
分子生物学
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癌症研究
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生物化学
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细胞生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2023
·Vol. 14
·期 2
·1-14
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IF 9
Zhang Shouyi,Lv Chengcheng,Niu Yichen,Li Changqi,Li Xiuming,Shang Yu,Zhang Yunchao,Zhang Yue,Zhang Yong,Zeng Yu
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m 6 A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
PLANT PHYSIOLOGY
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2023
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IF 7.4
Xu Jidi,He Jieqiang,Hu Bichun,Hou Nan,Guo Junxing,Wang Caixia,Li Xuewei,Li Zhongxing,Zhai Jingjing,Zhang Ting,Ma Chuang,Ma Fengwang,Guan Qingmei
Grafting can facilitate better scion performance and is widely used in plants. Numerous studies have studied the involvement of mRNAs, small RNAs, and epigenetic regulations in the grafting process. However, it remains unclear whether the mRNA N6-methyladenosine (m6A) modification participates in the apple (Malus x domestica Borkh.) grafting process. Here, we decoded the landscape of m6A modification profiles in ‘Golden delicious’ (a cultivar, Gd) and Malus prunifolia ‘Fupingqiuzi’ (a unique rootstock with resistance to environmental stresses, Mp), as well as their heterografted and self-grafted plants. Interestingly, global hypermethylation of m6A occurred in both heterografted scion and rootstock compared with their self-grafting controls. Gene Ontology (GO) term enrichment analysis showed that grafting-induced differentially m6A-modified genes were mainly involved in RNA processing, epigenetic regulation, stress response, and development. Differentially m6A-modified genes harboring expression alterations were mainly involved in various stress responses and fatty acid metabolism. Furthermore, grafting-induced mobile mRNAs with m6A and gene expression alterations mainly participated in ABA synthesis and transport (e.g. carotenoid cleavage dioxygenase 1 [CCD1] and ATP-binding cassette G22 [ABCG22]) and abiotic and biotic stress responses, which might contribute to the better performance of heterografted plants. Additionally, the DNA methylome analysis also demonstrated the DNA methylation alterations during grafting. Downregulated expression of m6A methyltransferase gene MdMTA (ortholog of METTL3) in apples induced the global m6A hypomethylation and distinctly activated the expression level of DNA demethylase gene MdROS1 (REPRESSOR OF SILENCING 1) showing the possible association between m6A and 5mC methylation in apples. Our results reveal the m6A modification profiles in the apple grafting process and enhance our understanding of the m6A regulatory mechanism in plant biological processes.
研究领域:
植物生物学
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表观遗传学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 7
·1-22
·
IF 8.1
Tan Diaoyi,Miao Daojia,Zhao Chuanyi,Shi Jian,Lv Qingyang,Lu Feiyi,Ruan Hailong,Xiong Zhiyong,Zhang Xiaoping
Aldehyde dehydrogenases superfamily (ALDHs), which are ubiquitously present in various organisms with diverse subcellular localizations, play a crucial role in regulating malignant tumor progression; Nevertheless, their involvement in clear cell renal cell carcinoma (ccRCC) has not been elucidated. In this study, we performed comprehensive bioinformatics analyses on the 19 ALDHs genes, and identified ALDH9A1 as a key contributor in ccRCC. Expression patterns and clinical relevance of ALDH9A1 were determined using bioinformatics analyses, real-time PCR, western blotting, and immunohistochemistry. To explore the underlying mechanism behind the tumor suppressor role of ALDH9A1, RNA sequencing, methylated RNA immunoprecipitation, luciferase reporter assay, mass spectroscopy, immunoprecipitation, mutational studies and immunofluorescence were employed. The impact of ALDH9A1 in ccRCC progression and metabolic programming was assessed through both in vitro and in vivo. Here, this study revealed ALDH9A1 as a tumor suppressor gene in ccRCC. The fat mass and obesity associated protein (FTO) was identified as a demethylase for ALDH9A1 mRNA, resulting in its reduced stability and expression levels in ccRCC. Functional experiments demonstrated that the deficiency of ALDH9A1 in ccRCC promoted tumor proliferation, invasion, migration and lipid accumulation. Mechanistic insights illustrated that the diminished levels of ALDH9A1 resulted in the failure to sequester nucleophosmin 1 (NPM1) within cytoplasm, thereby suppressing the transcription of IQ motif containing the GTPase-activating protein 2 (IQGAP2), subsequently activating the AKT-mTOR signaling, ultimately fostering tumor progression and lipid accumulation. In conclusion, the present study highlights the robust prognostic significance of ALDH9A1 and delivers a comprehensive understanding of ALDH9A1-NPM1-IQGAP2-AKT axis in ccRCC. These findings established a solid research foundation for novel therapeutic strategies for ccRCC patients.
研究领域:
癌症生物学
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分子生物学
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生物信息学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 4
·480-502
·
IF 16.2
Daojia Miao,Qi Wang,Jian Shi,Qingyang Lv,Diaoyi Tan,Chuanyi Zhao,Zhiyong Xiong,Xiaoping Zhang
Background The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients. Methods Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 ( DBT ) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies. Results DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m 6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes. Conclusions This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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代谢组学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
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