The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyl...Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.展开更多
Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long ...Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.展开更多
N^6-methyladenosine （m^6A） is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism, m^6A modification could be installed by m^6A ＂writ...N^6-methyladenosine （m^6A） is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism, m^6A modification could be installed by m^6A ＂writers＂ composed of core catalytic components （METTL3/METTL14/WTAP） and newly defined regulators and removed by m^6A ＂erasers＂ （FTO and ALKBH5）. The function of m^6A is executed by m^6A ＂readers＂ that bind to m^6A directly （YTH domain-containing proteins, eIF3 and IGF2BPs） or indirectly （HNRNPA2B1）. In the past few years, advances in m^6A modulators （＂writers,＂ ＂erasers,＂ and ＂readers＂） have remarkably renewed our understanding of the function and regulation of m^6A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m^6A are still largely unknown. Moreover, investigations of the m^6A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m^6A research and highlight the functional relevance and importance of m^6A modification in in vitro cell lines, in physiological contexts, and in cancers.展开更多
Silica fibers were modified by a specific ratio of SiB6 mixed with silica sol through vacuum impregnation method.The modified fibers were then incorporated into a phenolic resin matrix to prepare fiber-reinforced resi...Silica fibers were modified by a specific ratio of SiB6 mixed with silica sol through vacuum impregnation method.The modified fibers were then incorporated into a phenolic resin matrix to prepare fiber-reinforced resin composites.The influences of the SiB_(6)/SiO_(2)mixed modification on silica fiber properties were analyzed through thermogravimetric analysis(TGA),differential scanning calorimetry(DSC),scanning electron microscopy(SEM),and X-ray diffraction(XRD),respectively.Additionally,the influence of the SiB_(6)/SiO_(2)mixed modification on the mechanical properties of phenolic resin matrix composites was evaluated through mechanical testing.The experimeatal results indicate that the SiB_(6)/SiO_(2)mixed surface modification shows significant improvement in strength at room temperature and high temperatures,and crystallization temperature of silica fiber increases.The SiB_(6)/Silica sol co-modified silica fiber shows potential for future application in thermal protection and other high-temperature conditions.展开更多
NORHA,a long non-coding RNA(lncRNA),serves as a key inducer of follicular atresia in sows by triggering granulosa cells(GCs)apoptosis.However,its regulation by N6-methyladenosine(m6A)-the most abundant RNA modificatio...NORHA,a long non-coding RNA(lncRNA),serves as a key inducer of follicular atresia in sows by triggering granulosa cells(GCs)apoptosis.However,its regulation by N6-methyladenosine(m6A)-the most abundant RNA modification-remains unresolved.This study identified NORHA as a functional target of the m6A reader HNRNPA2B1 in sow GCs(sGCs).Transcriptome-wide mapping of RNA modification sites revealed extensive m6A enrichment on NORHA,with HNRNPA2B1 binding directly to the transcript and enhancing its stability via modification of multiple m6A sites,including A261,A441,and A919.HNRNPA2B1 suppressed 17β-estradiol(E2)biosynthesis and promoted sGC apoptosis by activating the NORHA-FoxO1 axis.FoxO1 subsequently repressed expression of cytochrome P450 family 19 subfamily A member 1(CYP19A1),which encodes the enzyme essential for E2 biosynthesis.Additionally,HNRNPA2B1 functioned as a critical mediator of METTL3-dependent m6A modification,modulating NORHA expression and activity in sGCs.This study highlights an important m6Adependent regulatory mechanism governing NORHA expression in sGCs.展开更多
The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molec...The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molecular to phenotypic alterations,while simultaneously exerting toxic effects on healthy tissue.N^(6)-methyladenosine(m^(6)A),a prevalent modification on coding and non-coding RNAs,is a key epigenetic mark established by a set of evolutionarily conserved enzymes.The interplay between m^(6)A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation.This review summarizes the roles of m^(6)A in the biological effects induced by ionizing radiation and ultraviolet(UV)radiation.It begins with an overview of m^(6)A modification and its detection methods,followed by a detailed examination of how m^(6)A dynamically regulates the sensitivity of cancerous tissues to RT,the injury response in non-cancerous tissues,and the toxicological effects of UV exposure.Notably,this review underscores the importance of novel regulatory mechanisms of m^(6)A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages.In conclusion,enzyme-mediated m^(6)A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs,thus modulating progression and radiosensitivity in cancerous tissues,as well as radiation effects on normal tissues.Several promising avenues for future research are further discussed.This review highlights the importance of m^(6)A modification in the context of radiation biology.Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.展开更多
The m^6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only so...The m^6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m^6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m^6A modification （m^6Afreq genes） and those occasionally regulated by m^6A modification （m^6Aocca genes）. Compared to the m^6Aocca genes, the m^6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein-protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m^6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m^6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m^6A epitranscriptomic regulation and other gene expression regulatory machineries.展开更多
Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping...Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types.展开更多
Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remai...Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remains high.Therefore,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic approaches.This study aims to explore the involvement of N6-methyladenosine(m^(6)A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear cholesteatoma.Methods:The m^(6)A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m^(6)A transcriptome microarray.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear cholesteatoma.Methylated RNA immunoprecipitation(MeRIP)-PCR was used to validate the m^(6)A modifications in cholesteatoma and normal skin tissues.Results:Compared with normal skin tissues,1525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activity.Hypomethylated lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA methylation.KEGG analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in cardiomyocytes.Hypomethylated lncRNAs were mainly involved in 4 pathways:Renal cell carcinoma,tumor necrosis factor signaling pathway,transcriptional misregulation in cancer,and cytokine-cytokine receptor interaction.Additionally,MeRIP-PCR confirmed the changes in m^(6)A methylation levels in NR_033339,NR_122111,NR_130744,and NR_026800,consistent with microarray analysis.Real-time PCR also confirmed the significant upregulation of MAPK1 and NF-κB,key genes in the MAPK signaling pathway.Conclusion:This study reveals the m^(6)A modification patterns of lncRNAs in middle ear cholesteatoma,suggests a direction for further research into the role of lncRNA m^(6)A modification in the etiology of cholesteatoma.The findings provide potential therapeutic targets for the treatment of middle ear cholesteatoma.展开更多
Objective:To explore the effects of N6-methyladenine(m^(6)A)modification-related genes,methyltransferase 14(METTL14),and YTH domain family protein 1(YTHDF1),on the proliferation,migration and apoptosis capabilities of...Objective:To explore the effects of N6-methyladenine(m^(6)A)modification-related genes,methyltransferase 14(METTL14),and YTH domain family protein 1(YTHDF1),on the proliferation,migration and apoptosis capabilities of cervical cancer cells and investigate their correlation with programmed cell death-ligand 1(PD-L1)expression.Methods:The expression levels of METTL14,YTHDF1 and PD-L1 in cervical cancer tissues and normal cervical tissues were analyzed using immunohistochemistry.Small interfering RNA(siRNA)was used to knock down the expression of METTL14 and YTHDF1 genes in cervical cancer cells,and the knockdown efficiency was validated by real-time fluorescent quantitative PCR(qPCR).After knockdown of METTL14 and YTHDF1,cell proliferation was assessed by CCK-8 assay,cell migration was examined by Transwell assay,cell apoptosis was detected by flow cytometry,and PD-L1 mRNA and protein expression were evaluated using qPCR and Western blotting,respectively.Results:Immunohistochemistry results demonstrated high expression of METTL14,YTHDF1,and PD-L1 in cervical cancer tissues.Knockdown of METTL14 and YTHDF1 significantly inhibited the proliferation and migration capabilities of cervical cancer cells,increased apoptosis,and downregulated PD-L1 mRNA and protein expression levels.Conclusion:m^(6)A methylation modification can affect the proliferation,migration and apoptosis of cervical cancer cells by regulating the expression of PD-L1 in cervical cancer cells.展开更多
目的:低风险微小乳头状甲状腺癌(papillary thyroid carcinoma,PTC)的检出增加与过度诊断和治疗有关。N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)修饰导致的微RNA(microRNAs,miRNA)失调在肿瘤转移和进展中发挥重要作用。然而,m^(6)...目的:低风险微小乳头状甲状腺癌(papillary thyroid carcinoma,PTC)的检出增加与过度诊断和治疗有关。N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)修饰导致的微RNA(microRNAs,miRNA)失调在肿瘤转移和进展中发挥重要作用。然而,m^(6)A靶向miRNAs在PTC中的功能仍不清楚。本研究旨在探究m^(6)A-miR-139-5p在PTC中的表达调控机制,明确其与PTC转移的关联,并评估其作为PTC转移诊断生物标志物的潜力,为PTC的精准诊断和治疗提供实验依据。方法:通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)和GSE130512队列筛选与PTC转移相关的候选靶向m^(6)A-miRNA分子。收集13例PTC转移患者和18例非转移患者的临床标本,检测m^(6)A-miR-139-5p的表达水平,分析其与转移的相关性。通过实验探究脂肪质量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)对pri-miR-139甲基化水平及加工过程的影响,明确其对miR-139-5p表达的调控作用。在TPC-1细胞中,通过四甲基偶氮唑盐(methyl thiazolyl tetrazolium,MTT)实验检测miR-139-5p过表达对FTO过表达介导的细胞增殖的影响。通过细胞侵袭实验验证miR-139-5p对PTC细胞侵袭能力的作用,并探究其是否通过靶向ZEB1/E-钙黏蛋白轴发挥功能。结果:通过比较TCGA和GSE130512队列,发现血清循环m^(6)A-miR-139-5p可作为检测PTC转移的生物指标。对13例转移和18例非转移临床标本的检测表明,FTO通过降低其甲基化水平抑制pri-miR-139的加工,导致miR-139-5p在PTC中表达失调(P<0.05)。在TPC-1细胞中,MTT实验显示miR-139-5p过表达可部分逆转FTO过表达介导的细胞增殖(P<0.05)。此外,miR-139-5p通过靶向ZEB1/E-钙黏蛋白轴抑制PTC细胞的侵袭能力,而FTO过表达可部分削弱这种抑制效应。结论:血清循环miR-139-5p可作为评估PTC转移的潜在标志物,FTO通过调控pri-miR-139的m^(6)A修饰影响miR-139-5的表达及功能,但其临床价值需进一步验证。展开更多
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金supported by the National Natural Science Foundation of China,Nos.82030071(to JH),82272495(to YC)Science and Technology Major Project of Changsha,No.kh2103008(to JH)Graduate Students’Independent Innovative Projects of Hunan Province,No.CX20230311(to YJ)。
文摘Spinal cord injury typically causes corticospinal tract disruption.Although the disrupted corticospinal tract can self-regenerate to a certain degree,the underlying mechanism of this process is still unclear.N6-methyladenosine(m^(6)A)modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes.However,whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown.We found that expression of methyltransferase 14 protein(METTL14)in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels.Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury.Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction,we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner,thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration.Finally,we administered syringin,a stabilizer of METTL14,using molecular docking.Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14.Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.
基金supported by the National Key R&D Program of China(2023YFD1300103)the Science and Technology Plan Project of Yantai City(2023ZDCX024)+5 种基金the National Natural Science Foundation of China(32372852)the Science Fund for Distinguished Young Scholars of Shaanxi Province(2024JC-JCQN-30)Shaanxi Provincial Innovation Leadership Program in Sciences and Technologies for Young and Middle-aged Scientists(2023SR205)the China Agriculture Research System-beef(CARS-37)the Innovation Team of Cattle Industry in Technological System of Shandong Modern Agriculture Industry(SDAIT-09-03)the Key Research and Development Project in Shandong Province(Competitive Innovation Platform)(2022CXPT010).
文摘Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.
基金This work was supported by the National Natural Science Foundation of China （No. 91753141 to Hua-Bing Li）.
文摘N^6-methyladenosine （m^6A） is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism, m^6A modification could be installed by m^6A ＂writers＂ composed of core catalytic components （METTL3/METTL14/WTAP） and newly defined regulators and removed by m^6A ＂erasers＂ （FTO and ALKBH5）. The function of m^6A is executed by m^6A ＂readers＂ that bind to m^6A directly （YTH domain-containing proteins, eIF3 and IGF2BPs） or indirectly （HNRNPA2B1）. In the past few years, advances in m^6A modulators （＂writers,＂ ＂erasers,＂ and ＂readers＂） have remarkably renewed our understanding of the function and regulation of m^6A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m^6A are still largely unknown. Moreover, investigations of the m^6A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m^6A research and highlight the functional relevance and importance of m^6A modification in in vitro cell lines, in physiological contexts, and in cancers.
基金Funded by the Natural Science Foundation of Hubei Province(No.2024AFB833)。
文摘Silica fibers were modified by a specific ratio of SiB6 mixed with silica sol through vacuum impregnation method.The modified fibers were then incorporated into a phenolic resin matrix to prepare fiber-reinforced resin composites.The influences of the SiB_(6)/SiO_(2)mixed modification on silica fiber properties were analyzed through thermogravimetric analysis(TGA),differential scanning calorimetry(DSC),scanning electron microscopy(SEM),and X-ray diffraction(XRD),respectively.Additionally,the influence of the SiB_(6)/SiO_(2)mixed modification on the mechanical properties of phenolic resin matrix composites was evaluated through mechanical testing.The experimeatal results indicate that the SiB_(6)/SiO_(2)mixed surface modification shows significant improvement in strength at room temperature and high temperatures,and crystallization temperature of silica fiber increases.The SiB_(6)/Silica sol co-modified silica fiber shows potential for future application in thermal protection and other high-temperature conditions.
基金supported by the National Natural Science Foundation of China(32072693)Fundamental Research Funds for the Central Universities(KYLH2025010)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX24-0994)。
文摘NORHA,a long non-coding RNA(lncRNA),serves as a key inducer of follicular atresia in sows by triggering granulosa cells(GCs)apoptosis.However,its regulation by N6-methyladenosine(m6A)-the most abundant RNA modification-remains unresolved.This study identified NORHA as a functional target of the m6A reader HNRNPA2B1 in sow GCs(sGCs).Transcriptome-wide mapping of RNA modification sites revealed extensive m6A enrichment on NORHA,with HNRNPA2B1 binding directly to the transcript and enhancing its stability via modification of multiple m6A sites,including A261,A441,and A919.HNRNPA2B1 suppressed 17β-estradiol(E2)biosynthesis and promoted sGC apoptosis by activating the NORHA-FoxO1 axis.FoxO1 subsequently repressed expression of cytochrome P450 family 19 subfamily A member 1(CYP19A1),which encodes the enzyme essential for E2 biosynthesis.Additionally,HNRNPA2B1 functioned as a critical mediator of METTL3-dependent m6A modification,modulating NORHA expression and activity in sGCs.This study highlights an important m6Adependent regulatory mechanism governing NORHA expression in sGCs.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82173467 and 82273577)CAMS Innovation Fund for Medical Sciences(Grant Nos.CIFMS,2022-I2M-2-003 and 2021-I2M-1-042).
文摘The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues.Radiation therapy(RT)induces oncological responses,from molecular to phenotypic alterations,while simultaneously exerting toxic effects on healthy tissue.N^(6)-methyladenosine(m^(6)A),a prevalent modification on coding and non-coding RNAs,is a key epigenetic mark established by a set of evolutionarily conserved enzymes.The interplay between m^(6)A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation.This review summarizes the roles of m^(6)A in the biological effects induced by ionizing radiation and ultraviolet(UV)radiation.It begins with an overview of m^(6)A modification and its detection methods,followed by a detailed examination of how m^(6)A dynamically regulates the sensitivity of cancerous tissues to RT,the injury response in non-cancerous tissues,and the toxicological effects of UV exposure.Notably,this review underscores the importance of novel regulatory mechanisms of m^(6)A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages.In conclusion,enzyme-mediated m^(6)A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs,thus modulating progression and radiosensitivity in cancerous tissues,as well as radiation effects on normal tissues.Several promising avenues for future research are further discussed.This review highlights the importance of m^(6)A modification in the context of radiation biology.Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.
基金supported by the National Natural Science Foundation of China (Grant Nos. 81670462 and 81422006 to QC)China Postdoctoral Science Foundation (Grant No. 2016M591024 to YZ)
文摘The m^6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m^6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m^6A modification （m^6Afreq genes） and those occasionally regulated by m^6A modification （m^6Aocca genes）. Compared to the m^6Aocca genes, the m^6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein-protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m^6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m^6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m^6A epitranscriptomic regulation and other gene expression regulatory machineries.
基金This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.81922052,81974435,and 81772999)Natural Science Foundation of Guangdong Province(Grant No.2019B151502011)the Guangzhou People’s Livelihood Science and Technology Project(Grant No.201903010006).
文摘Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types.
基金supported by the National Natural Science Foundation(82071036,82000973)the Natural Science Foundation of Hunan Province(2022JJ30821,2019JJ50967)the Special Project for the Construction of Innovative Provinces in Hunan Province(2023SK4030),China。
文摘Objective:Middle ear cholesteatoma is a non-tumorous condition that typically leads to hearing loss,bone destruction,and other severe complications.Despite surgery being the primary treatment,the recurrence rate remains high.Therefore,exploring the molecular mechanisms underlying cholesteatoma is crucial for discovering new therapeutic approaches.This study aims to explore the involvement of N6-methyladenosine(m^(6)A)methylation in long non-coding RNAs(lncRNAs)in the biological functions and related pathways of middle ear cholesteatoma.Methods:The m^(6)A modification patterns of lncRNA in middle ear cholesteatoma tissues(n=5)and normal post-auricular skin tissues(n=5)were analyzed using an lncRNA m^(6)A transcriptome microarray.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to identify potential biological functions and signaling pathways involved in the pathogenesis of middle ear cholesteatoma.Methylated RNA immunoprecipitation(MeRIP)-PCR was used to validate the m^(6)A modifications in cholesteatoma and normal skin tissues.Results:Compared with normal skin tissues,1525 lncRNAs were differentially methylated in middle ear cholesteatoma tissues,with 1048 showing hypermethylation and 477 showing hypomethylation[fold change(FC)≥3 or<1/3,P<0.05].GO enrichment analysis indicated that hypermethylated lncRNAs were involved in protein phosphatase inhibitor activity,neuron-neuron synapse,and regulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)receptor activity.Hypomethylated lncRNAs were associated with mRNA methyltransferase activity,secretory granule membrane,and mRNA methylation.KEGG analysis revealed that hypermethylated lncRNAs were mainly associated with 5 pathways:the Hedgehog signaling pathway,viral protein interaction with cytokines and cytokine receptors,mitogen-activated protein kinase(MAPK)signaling pathway,cytokine-cytokine receptor interaction,and adrenergic signaling in cardiomyocytes.Hypomethylated lncRNAs were mainly involved in 4 pathways:Renal cell carcinoma,tumor necrosis factor signaling pathway,transcriptional misregulation in cancer,and cytokine-cytokine receptor interaction.Additionally,MeRIP-PCR confirmed the changes in m^(6)A methylation levels in NR_033339,NR_122111,NR_130744,and NR_026800,consistent with microarray analysis.Real-time PCR also confirmed the significant upregulation of MAPK1 and NF-κB,key genes in the MAPK signaling pathway.Conclusion:This study reveals the m^(6)A modification patterns of lncRNAs in middle ear cholesteatoma,suggests a direction for further research into the role of lncRNA m^(6)A modification in the etiology of cholesteatoma.The findings provide potential therapeutic targets for the treatment of middle ear cholesteatoma.
基金National Natural Science Foundation of China (No.81472431)Jiangsu Provincial Medical Key Talent Fund (No.ZDRCA2016072)Natural Science Foundation of Nanjing University of Traditional Chinese Medicine (No.XZR2020070)。
文摘Objective:To explore the effects of N6-methyladenine(m^(6)A)modification-related genes,methyltransferase 14(METTL14),and YTH domain family protein 1(YTHDF1),on the proliferation,migration and apoptosis capabilities of cervical cancer cells and investigate their correlation with programmed cell death-ligand 1(PD-L1)expression.Methods:The expression levels of METTL14,YTHDF1 and PD-L1 in cervical cancer tissues and normal cervical tissues were analyzed using immunohistochemistry.Small interfering RNA(siRNA)was used to knock down the expression of METTL14 and YTHDF1 genes in cervical cancer cells,and the knockdown efficiency was validated by real-time fluorescent quantitative PCR(qPCR).After knockdown of METTL14 and YTHDF1,cell proliferation was assessed by CCK-8 assay,cell migration was examined by Transwell assay,cell apoptosis was detected by flow cytometry,and PD-L1 mRNA and protein expression were evaluated using qPCR and Western blotting,respectively.Results:Immunohistochemistry results demonstrated high expression of METTL14,YTHDF1,and PD-L1 in cervical cancer tissues.Knockdown of METTL14 and YTHDF1 significantly inhibited the proliferation and migration capabilities of cervical cancer cells,increased apoptosis,and downregulated PD-L1 mRNA and protein expression levels.Conclusion:m^(6)A methylation modification can affect the proliferation,migration and apoptosis of cervical cancer cells by regulating the expression of PD-L1 in cervical cancer cells.
文摘目的:低风险微小乳头状甲状腺癌(papillary thyroid carcinoma,PTC)的检出增加与过度诊断和治疗有关。N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)修饰导致的微RNA(microRNAs,miRNA)失调在肿瘤转移和进展中发挥重要作用。然而,m^(6)A靶向miRNAs在PTC中的功能仍不清楚。本研究旨在探究m^(6)A-miR-139-5p在PTC中的表达调控机制,明确其与PTC转移的关联,并评估其作为PTC转移诊断生物标志物的潜力,为PTC的精准诊断和治疗提供实验依据。方法:通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)和GSE130512队列筛选与PTC转移相关的候选靶向m^(6)A-miRNA分子。收集13例PTC转移患者和18例非转移患者的临床标本,检测m^(6)A-miR-139-5p的表达水平,分析其与转移的相关性。通过实验探究脂肪质量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)对pri-miR-139甲基化水平及加工过程的影响,明确其对miR-139-5p表达的调控作用。在TPC-1细胞中,通过四甲基偶氮唑盐(methyl thiazolyl tetrazolium,MTT)实验检测miR-139-5p过表达对FTO过表达介导的细胞增殖的影响。通过细胞侵袭实验验证miR-139-5p对PTC细胞侵袭能力的作用,并探究其是否通过靶向ZEB1/E-钙黏蛋白轴发挥功能。结果:通过比较TCGA和GSE130512队列,发现血清循环m^(6)A-miR-139-5p可作为检测PTC转移的生物指标。对13例转移和18例非转移临床标本的检测表明,FTO通过降低其甲基化水平抑制pri-miR-139的加工,导致miR-139-5p在PTC中表达失调(P<0.05)。在TPC-1细胞中,MTT实验显示miR-139-5p过表达可部分逆转FTO过表达介导的细胞增殖(P<0.05)。此外,miR-139-5p通过靶向ZEB1/E-钙黏蛋白轴抑制PTC细胞的侵袭能力,而FTO过表达可部分削弱这种抑制效应。结论:血清循环miR-139-5p可作为评估PTC转移的潜在标志物,FTO通过调控pri-miR-139的m^(6)A修饰影响miR-139-5的表达及功能,但其临床价值需进一步验证。
