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 latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A...The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.展开更多
In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted t...In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing,with particular emphasis on DNA and RNA methylation pathways.This editorial discusses the findings of Xiao et al,who identified the Wilms tumor 1-associated protein(WTAP)-DNA methyltransferase 1(DNMT1)axis as a pivotal regulator of endothelial dys-function in DFUs.WTAP,a regulatory subunit of N6-methyladenosine(m6A)methyltransferase,is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification.This contributes to im-paired angiogenesis,reduced cell viability,and delayed wound closure.WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model.Furthermore,DNMT1 overexpression ab-rogated the benefits of WTAP suppression,confirming its downstream effector role.Thus,targeting the WTAP-DNMT1 axis provides a new avenue for DFU management.Moreover,epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.展开更多
Background Liver ischemia/reperfusion(I/R)injury is usually caused by hepatic inflow occlusion during liver surgery,and is frequently observed during war wounds and trauma.Hepatocyte ferroptosis plays a critical role ...Background Liver ischemia/reperfusion(I/R)injury is usually caused by hepatic inflow occlusion during liver surgery,and is frequently observed during war wounds and trauma.Hepatocyte ferroptosis plays a critical role in liver I/R injury,however,it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase(DDX/DHX)family.Methods The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis.Hepatocyte-specific Dhx58 knockout mice were constructed,and a partial liver I/R operation was performed.Single-cell RNA sequencing(scRNA-seq)in the liver post I/R suggested enhanced ferroptosis by Dhx58hep−/−.The mRNAs and proteins associated with DExH-box helicase 58(DHX58)were screened using RNA immunoprecipitation-sequencing(RIP-seq)and IP-mass spectrometry(IP-MS).Results Excessive production of reactive oxygen species(ROS)decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis,while treatment using IFN-αincreased DHX58 expression and prevented ferroptosis during liver I/R injury.Mechanistically,DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4(GPX4),a central ferroptosis suppressor,and recruits the m6A reader YT521-B homology domain containing 2(YTHDC2)to promote the translation of Gpx4 mRNA in an m6A-dependent manner,thus enhancing GPX4 protein levels and preventing hepatic ferroptosis.Conclusions This study provides mechanistic evidence that IFN-αstimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA,suggesting the potential clinical application of IFN-αin the prevention of hepatic ferroptosis during liver I/R injury.展开更多
Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more ...Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.展开更多
N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles...N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles of m6A modification owing to their great importance in biological significance.The abnormal regulation of m6A modification will lead to aberrant cellular behavior and various diseases.Recently,studies have demonstrated that m6A modification is closely associated with the genesis and progression of ocular surface diseases(OSDs).This review focus on the role of m6A modification and research progress in OSDs including fungal keratitis,herpes simplex keratitis,immunerelated keratoconjunctival diseases,pterygium,ocular chemical burns,and Graves’ophthalmopathy,which may provide new insights into and prospective applications for OSDs.展开更多
N6-methyladenosine(m6A)is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs,affecting its target gene expression by controlling RNA localization,splicing,stability,and translation.m6...N6-methyladenosine(m6A)is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs,affecting its target gene expression by controlling RNA localization,splicing,stability,and translation.m6A modifications are regulated by m6A methyltransferase complex,demethylase,and reading proteins.Insulin-like growth factor-2 mRNA-binding protein 1(IGF2BP1),a member of a conserved family of single-stranded RNA-binding proteins,has recently been identified as a vital m6A reading protein.IGF2BP1 is highly expressed in various tumors and is associated with poor prognosis and treatment resistance.Furthermore,previous studies have shown that IGF2BP1 plays critical roles in regulating various cancer hallmarks,including sustained cell proliferation,cell death resistance,activation of invasion and metastasis,deregulated cellular energetics,immune evasion,and unlocking phenotypic plasticity.IGF2BP1 could promote the expression of cancer-related genes by recognizing their m6A sites,thereby altering cell characteristics,and eventually,malignancy.Therefore,IGF2BP1 might be a potential target for tumor diagnosis and anti-tumor therapeutic strategies.This review summarizes the current knowledge on the functional roles and underlying molecular mechanisms of IGF2BP1 in regulating cancer hallmarks.Moreover,we discuss the prospects of IGF2BP1 as a potential tumor diagnosis marker,as well as a potential target for an anti-tumor therapeutic strategy.展开更多
N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and...N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and thus,plays a significant role in basic life processes.Numerous studies on m6A modification identified FTO as a crucial demethylase that participates in various biological processes.Not only does FTO play a pivotal role in obesity-related conditions,but it also influences the occurrence,development,and prognosis of several cancers,such as acute myeloid leukemia,breast cancer,liver cancer,and lung cancer.Moreover,FTO also shows a close association with immunity and viral infections.This article summarized the molecular mechanism of FTO in tumorigenesis and tumor progression.展开更多
Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the preci...Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.展开更多
Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose postt...Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.展开更多
N6-methyladenosine(m^(6)A)is the most abundant internal modification on RNA.It is a dynamical and reversible process,which is regulated by m^(6)A methyltransferase and m^(6)A demethylase.The m^(6)A modified RNA can be...N6-methyladenosine(m^(6)A)is the most abundant internal modification on RNA.It is a dynamical and reversible process,which is regulated by m^(6)A methyltransferase and m^(6)A demethylase.The m^(6)A modified RNA can be specifically recognized by the m^(6)A reader,leading to RNA splicing,maturation,degradation or translation.The abnormality of m^(6)A RNA modification is closely related to a variety of biological processes,especially the occurrence and development of tumors.Recent studies have shown that m^(6)A RNA modification is involved in the pathogenesis of skin cancers.However,the precise molecular mechanisms of m^(6)A-mediated cutaneous tumorigenesis have not been fully elucidated.Therefore,this review will summarize the biological characteristics of m^(6)A modification,its regulatory role and mechanism in skin cancers,and the recent research progress of m^(6)A-related molecular drugs,aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.展开更多
Increasing evidence indicates that N6-methyladenosine(m6A)methylation modification serves important functions in biological metabolism.Dysregulation of m6A regulators is related to the progression of different maligna...Increasing evidence indicates that N6-methyladenosine(m6A)methylation modification serves important functions in biological metabolism.Dysregulation of m6A regulators is related to the progression of different malignancies,including renal cell carcinoma(RCC).Recent studies have reported preliminary findings on the influence of m6A regulator dysregulation on RCC tumorigenesis and development.However,no comprehensive review that integrates and analyzes the roles of m6A modification in RCC has been published to date.In this review,we focus on the dysregulation of m6A regulators as it relates to RCC tumorigenesis and development,as well as possible applications of m6A modification in RCC diagnosis and therapeutics.展开更多
Intestinal epithelial cells(IECs)are pivotal for maintaining intestinal homeostasis through self-renewal,proliferation,differentiation,and regulated cell death.While apoptosis and necroptosis are recognized as distinc...Intestinal epithelial cells(IECs)are pivotal for maintaining intestinal homeostasis through self-renewal,proliferation,differentiation,and regulated cell death.While apoptosis and necroptosis are recognized as distinct pathways,their intricate interplay remains elusive.In this study,we report that Mettl3-mediatedm6A modification maintains intesti-nal homeostasis by impeding epithelial cell death.Mettl3 knockout induces both apoptosis and necroptosis in IECs.Targeting different modes of cell death with specific inhibitors unveils that RIPK1 kinase activity is critical for the cell death triggered by Mettl3 knockout.Mechanistically,this occurs via them6A-mediated transcriptional regulation of Atf3,a transcription factor that directly binds to Cflar,the gene encoding the anti-cell death protein cFLIP.cFLIP inhibits RIPK1 activity,thereby suppressing downstream apoptotic and necroptotic signaling.Together,these find-ings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.展开更多
Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,i...Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,initially known as the obesity-related protein,is the first identified m6A demethylase.However,the relationship between FTO and breast cancer remains controversial.In this study,we aimed to elucidate the role and clinical significance of FTO in breast cancer and to explore the underlying mechanism.Methods:We first investigated the expression of FTO in breast cancer cell lines and tissues by quantitative reverse transcription-PCR(qRT-PCR),Western blotting,and immunohistochemistry.Wound healing assay and Transwell assay were performed to determine the migration and invasion abilities of SKBR3 and MDAMB453 cells with either knockdown or overexpression of FTO.RNA sequencing(RNA-seq)was conducted to decipher the downstream targets of FTO.qRT-PCR,luciferase reporter assay,and Western blotting were employed to confirm the existence of the FTO/miR-181b-3p/ARL5B axis.The biological function of ADP ribosylation factor like GTPase 5B(ARL5B)in breast cancer cells was evaluated by wound healing assay and Transwell invasion assay.Results:High FTO expression was observed in human epidermal growth factor receptor 2(HER2)-positive breast cancer,predicting advanced progression(tumor size[P<0.001],nuclear grade[P=0.001],peritumoral lymphovascular invasion[P<0.001),lymph node metastasis[P=0.002],and TNM stage[P=0.001])and poor prognosis.Moreover,FTO promoted cell invasion and migration in vitro.Mechanistically,RNA-seq and further confirmation studies suggested that FTO up-regulated ARL5B by inhibiting miR-181b-3p.We further verified that ARL5B also displayed carcinogenic activity in breast cancer cells.Conclusion:Our work demonstrated the carcinogenic activity of FTO in promoting the invasion and migration of breast cancer cells via the FTO/miR-181b-3p/ARL5B signaling pathway.展开更多
Obesity has become a major health crisis in the past∼50 years.The fat mass and obesity-associated(FTO)gene,identified by genome-wide association studies(GWAS),was first reported to be positively associated with obesi...Obesity has become a major health crisis in the past∼50 years.The fat mass and obesity-associated(FTO)gene,identified by genome-wide association studies(GWAS),was first reported to be positively associated with obesity in humans.Mice with more copies of the FTO gene were observed to be obese,while loss of the gene in mice was found to protect from obesity.Later,FTO was found to encode an m6 A RNA demethylase and has a profound effect on many biological and metabolic processes.In this review,we first summarize recent studies that demonstrate the critical roles and regulatory mechanisms of FTO in obesity and metabolic disease.Second,we discuss the ongoing debates concerning the association between FTO polymorphisms and obesity.Third,since several small molecule drugs and micronutrients have been found to regulate metabolic homeostasis through controlling the expression or activity of FTO,we highlight the broad potential of targeting FTO for obesity treatment.Improving our understanding of FTO and the underlying mechanisms may provide new approaches for treating obesity and metabolic diseases.展开更多
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This work was supported by grants from National Science Foundation of China(No.81671995)The Science Technology and Innovation Committee of Shenzhen Municipality(No.JCYJ20180507181627057)and Strategic funds from City University of Hong Kong.
文摘The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.
基金Supported by the Kuwait Foundation for the Advancement of Sciences and Dasman Diabetes Institute,No.RACB-2021-007.
文摘In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing,with particular emphasis on DNA and RNA methylation pathways.This editorial discusses the findings of Xiao et al,who identified the Wilms tumor 1-associated protein(WTAP)-DNA methyltransferase 1(DNMT1)axis as a pivotal regulator of endothelial dys-function in DFUs.WTAP,a regulatory subunit of N6-methyladenosine(m6A)methyltransferase,is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification.This contributes to im-paired angiogenesis,reduced cell viability,and delayed wound closure.WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model.Furthermore,DNMT1 overexpression ab-rogated the benefits of WTAP suppression,confirming its downstream effector role.Thus,targeting the WTAP-DNMT1 axis provides a new avenue for DFU management.Moreover,epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.
基金National Key Research and Development Program of China(2023YFC2505900)National Natural Science Foundation of China(92269204,82171755,92369106,82171749,82171811,82073184)+1 种基金Military Outstanding Youth Program(2020QN06119,01-SWK JYCJJ07,23SWAQ53)Program of Leading Talents in Shanghai,and Shanghai Shuguang Program(20SG39)。
文摘Background Liver ischemia/reperfusion(I/R)injury is usually caused by hepatic inflow occlusion during liver surgery,and is frequently observed during war wounds and trauma.Hepatocyte ferroptosis plays a critical role in liver I/R injury,however,it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase(DDX/DHX)family.Methods The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis.Hepatocyte-specific Dhx58 knockout mice were constructed,and a partial liver I/R operation was performed.Single-cell RNA sequencing(scRNA-seq)in the liver post I/R suggested enhanced ferroptosis by Dhx58hep−/−.The mRNAs and proteins associated with DExH-box helicase 58(DHX58)were screened using RNA immunoprecipitation-sequencing(RIP-seq)and IP-mass spectrometry(IP-MS).Results Excessive production of reactive oxygen species(ROS)decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis,while treatment using IFN-αincreased DHX58 expression and prevented ferroptosis during liver I/R injury.Mechanistically,DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4(GPX4),a central ferroptosis suppressor,and recruits the m6A reader YT521-B homology domain containing 2(YTHDC2)to promote the translation of Gpx4 mRNA in an m6A-dependent manner,thus enhancing GPX4 protein levels and preventing hepatic ferroptosis.Conclusions This study provides mechanistic evidence that IFN-αstimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA,suggesting the potential clinical application of IFN-αin the prevention of hepatic ferroptosis during liver I/R injury.
基金supported by the National Natural Science Foundation of China,No.82171062(to JFZ)Aier Eye Hospital Group Scientific Research Fund,No.AF2101D8(to LMG).
文摘Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.
基金Supported by Project of Shanghai Science and Technology (No.20ZR1443600)。
文摘N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles of m6A modification owing to their great importance in biological significance.The abnormal regulation of m6A modification will lead to aberrant cellular behavior and various diseases.Recently,studies have demonstrated that m6A modification is closely associated with the genesis and progression of ocular surface diseases(OSDs).This review focus on the role of m6A modification and research progress in OSDs including fungal keratitis,herpes simplex keratitis,immunerelated keratoconjunctival diseases,pterygium,ocular chemical burns,and Graves’ophthalmopathy,which may provide new insights into and prospective applications for OSDs.
基金supported by grants from the National Natural Science Foundation of China(No.82173029,32270778,and 82372655)the Natural Science Foundation of Chongqing,China(No.CSTB2022NSCQ-MSX0611,CSTB2022NSCQ-MSX0612)the Talent Project of Chongqing University Jiangjin Hospital(Chongqing,China)(No.2024LJXM005).
文摘N6-methyladenosine(m6A)is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs,affecting its target gene expression by controlling RNA localization,splicing,stability,and translation.m6A modifications are regulated by m6A methyltransferase complex,demethylase,and reading proteins.Insulin-like growth factor-2 mRNA-binding protein 1(IGF2BP1),a member of a conserved family of single-stranded RNA-binding proteins,has recently been identified as a vital m6A reading protein.IGF2BP1 is highly expressed in various tumors and is associated with poor prognosis and treatment resistance.Furthermore,previous studies have shown that IGF2BP1 plays critical roles in regulating various cancer hallmarks,including sustained cell proliferation,cell death resistance,activation of invasion and metastasis,deregulated cellular energetics,immune evasion,and unlocking phenotypic plasticity.IGF2BP1 could promote the expression of cancer-related genes by recognizing their m6A sites,thereby altering cell characteristics,and eventually,malignancy.Therefore,IGF2BP1 might be a potential target for tumor diagnosis and anti-tumor therapeutic strategies.This review summarizes the current knowledge on the functional roles and underlying molecular mechanisms of IGF2BP1 in regulating cancer hallmarks.Moreover,we discuss the prospects of IGF2BP1 as a potential tumor diagnosis marker,as well as a potential target for an anti-tumor therapeutic strategy.
基金This study was supported by the Natural Science Foundation of Guangdong Provincial(2019A1515011911)the Research Program of Shenzhen Innovation Council(JCYJ20200109140208058)+1 种基金the Sanming Project of Medicine in Shenzhen(SZSM202111012)the Oral and Maxillofacial Surgery Team,Professor Yu Guangyan,Stomatological Hospital Peking University,Guangdong Provincial High-Level Clinical Key Specialty(Shenzhen Matching Construction Fund)(Grant No.SZGSP008).
文摘N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and thus,plays a significant role in basic life processes.Numerous studies on m6A modification identified FTO as a crucial demethylase that participates in various biological processes.Not only does FTO play a pivotal role in obesity-related conditions,but it also influences the occurrence,development,and prognosis of several cancers,such as acute myeloid leukemia,breast cancer,liver cancer,and lung cancer.Moreover,FTO also shows a close association with immunity and viral infections.This article summarized the molecular mechanism of FTO in tumorigenesis and tumor progression.
基金supported by the National Natural Science Foundation of China(82172592)the Free Exploration Program of Central South University(2021zzts0934)the program of Introducing Talents of Discipline to Universities(111-2-12)。
文摘Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.
文摘Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.
基金supported by grants from the National Natural Science Foundation of China(No.82103726,82103727,and 81803138)Shenzhen Science and Technology Program,China(No.JCYJ20210324110008023)+2 种基金Shenzhen Sanming Project,China(No.SZSM201812059)Shenzhen Key Medical Discipline Construction Fund,China(No.SZXK040)Scientific Research Foundation of Peking University Shenzhen Hospital,China(No.KYQD2021016,KYQD2021038,KYQD2021039,KYQD2021049,and KYQD2021052).
文摘N6-methyladenosine(m^(6)A)is the most abundant internal modification on RNA.It is a dynamical and reversible process,which is regulated by m^(6)A methyltransferase and m^(6)A demethylase.The m^(6)A modified RNA can be specifically recognized by the m^(6)A reader,leading to RNA splicing,maturation,degradation or translation.The abnormality of m^(6)A RNA modification is closely related to a variety of biological processes,especially the occurrence and development of tumors.Recent studies have shown that m^(6)A RNA modification is involved in the pathogenesis of skin cancers.However,the precise molecular mechanisms of m^(6)A-mediated cutaneous tumorigenesis have not been fully elucidated.Therefore,this review will summarize the biological characteristics of m^(6)A modification,its regulatory role and mechanism in skin cancers,and the recent research progress of m^(6)A-related molecular drugs,aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.
基金funded by Shenzhen Basic Science Research(JCYJ20190809164617205)Sanming Project of Medicine in Shenzhen(SZSM202011011)Part-time PI Research Start-up Fund of SAHSYSU(ZSQYJZPI202003).
文摘Increasing evidence indicates that N6-methyladenosine(m6A)methylation modification serves important functions in biological metabolism.Dysregulation of m6A regulators is related to the progression of different malignancies,including renal cell carcinoma(RCC).Recent studies have reported preliminary findings on the influence of m6A regulator dysregulation on RCC tumorigenesis and development.However,no comprehensive review that integrates and analyzes the roles of m6A modification in RCC has been published to date.In this review,we focus on the dysregulation of m6A regulators as it relates to RCC tumorigenesis and development,as well as possible applications of m6A modification in RCC diagnosis and therapeutics.
基金National Natural Science Foundation of China(31988101 to YGC,92354306 to YL)National Key Research and Development Program of China(2023YFA1800603)+2 种基金Natural Science Foundation of Jiangxi Province(20224ACB209001)Beijing Science and Technology Plan(Z231100007223006)Shenzhen Medical Research Fund(B2302022)to YGC.
文摘Intestinal epithelial cells(IECs)are pivotal for maintaining intestinal homeostasis through self-renewal,proliferation,differentiation,and regulated cell death.While apoptosis and necroptosis are recognized as distinct pathways,their intricate interplay remains elusive.In this study,we report that Mettl3-mediatedm6A modification maintains intesti-nal homeostasis by impeding epithelial cell death.Mettl3 knockout induces both apoptosis and necroptosis in IECs.Targeting different modes of cell death with specific inhibitors unveils that RIPK1 kinase activity is critical for the cell death triggered by Mettl3 knockout.Mechanistically,this occurs via them6A-mediated transcriptional regulation of Atf3,a transcription factor that directly binds to Cflar,the gene encoding the anti-cell death protein cFLIP.cFLIP inhibits RIPK1 activity,thereby suppressing downstream apoptotic and necroptotic signaling.Together,these find-ings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.
文摘Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,initially known as the obesity-related protein,is the first identified m6A demethylase.However,the relationship between FTO and breast cancer remains controversial.In this study,we aimed to elucidate the role and clinical significance of FTO in breast cancer and to explore the underlying mechanism.Methods:We first investigated the expression of FTO in breast cancer cell lines and tissues by quantitative reverse transcription-PCR(qRT-PCR),Western blotting,and immunohistochemistry.Wound healing assay and Transwell assay were performed to determine the migration and invasion abilities of SKBR3 and MDAMB453 cells with either knockdown or overexpression of FTO.RNA sequencing(RNA-seq)was conducted to decipher the downstream targets of FTO.qRT-PCR,luciferase reporter assay,and Western blotting were employed to confirm the existence of the FTO/miR-181b-3p/ARL5B axis.The biological function of ADP ribosylation factor like GTPase 5B(ARL5B)in breast cancer cells was evaluated by wound healing assay and Transwell invasion assay.Results:High FTO expression was observed in human epidermal growth factor receptor 2(HER2)-positive breast cancer,predicting advanced progression(tumor size[P<0.001],nuclear grade[P=0.001],peritumoral lymphovascular invasion[P<0.001),lymph node metastasis[P=0.002],and TNM stage[P=0.001])and poor prognosis.Moreover,FTO promoted cell invasion and migration in vitro.Mechanistically,RNA-seq and further confirmation studies suggested that FTO up-regulated ARL5B by inhibiting miR-181b-3p.We further verified that ARL5B also displayed carcinogenic activity in breast cancer cells.Conclusion:Our work demonstrated the carcinogenic activity of FTO in promoting the invasion and migration of breast cancer cells via the FTO/miR-181b-3p/ARL5B signaling pathway.
基金supported by the National Key R&D Program(No.2018YFD0500405).
文摘Obesity has become a major health crisis in the past∼50 years.The fat mass and obesity-associated(FTO)gene,identified by genome-wide association studies(GWAS),was first reported to be positively associated with obesity in humans.Mice with more copies of the FTO gene were observed to be obese,while loss of the gene in mice was found to protect from obesity.Later,FTO was found to encode an m6 A RNA demethylase and has a profound effect on many biological and metabolic processes.In this review,we first summarize recent studies that demonstrate the critical roles and regulatory mechanisms of FTO in obesity and metabolic disease.Second,we discuss the ongoing debates concerning the association between FTO polymorphisms and obesity.Third,since several small molecule drugs and micronutrients have been found to regulate metabolic homeostasis through controlling the expression or activity of FTO,we highlight the broad potential of targeting FTO for obesity treatment.Improving our understanding of FTO and the underlying mechanisms may provide new approaches for treating obesity and metabolic diseases.
