Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA pr...Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA processing, and mRNA stability during RNA processing and translation. RNAs, especially mRNAs, are relatively vulnerable molecules in living cells for ribonucleases （RNases）. The maintenance of quality and quantity of transcripts is a key issue for many biological processes. Extensive studies draw the conclusion that the stability of RNAs is dedicated-regulated, occurring co- and post-transcriptionally, and translation-coupled as well, either in the nucleus or cytoplasm. Recently, RNA stability in the nucleus has aroused much research interest, especially the stability of newly-made transcripts. In this article, we summarize recent progresses on mRNA stability in the nucleus, especially focusing on quality control of newly-made RNA by RNA polymerase Ⅱ in eukaryotes.展开更多
Objective The initiation and progression of lung carcinomas are critically regulated by long non-coding RNAs(lncRNAs).However,the role of lncRNAs in the pathways causing lung cancer remains unknown.Methods Cell morpho...Objective The initiation and progression of lung carcinomas are critically regulated by long non-coding RNAs(lncRNAs).However,the role of lncRNAs in the pathways causing lung cancer remains unknown.Methods Cell morphology was regularly observed using an inverted phase-contrast microscope.Cell viability was assessed using CCK-8 according to the manufacturer’s instructions.Total RNA was retrotranscribed from each specimen using the RNAiso Plus Kit.The RT-PCR data were calculated using the Ct approach for comparison.Flow cytometric analyses were prepared by Click-iT™Plus TUNEL Assay for In Situ apoptosis detection,with Alexa Fluor^(TM)594 dye,as instructed.RNA immunoprecipitation assays were used to determine RNA concentration.Results Activated natural killer cells repeat and PH domain-containing protein 2 antisense RNA 1(AGAP2-AS1)levels in cancerous tissues were significantly correlated with cancerous tumor node metastasis(TNM)stage,with cancerous AGAP2-AS1 levels being higher in cancerous tissues than healthy tissues.Patients withelevated AGAP2-AS1 levels had considerably worse outcomes than those with reduced AGAP2-AS1 levels,regardless of the progression-free or overall survival.Functionally,AGAP2-AS1 downregulation represseslung cancer cell growth.AGAP2-AS1 elimination induces erastin-mediated ferroptosis in lung cancer cells.However,the ferritin inhibitor FERSINT-1 negated this result,whereas ERASTIN induced lung cancer cellmortality.After AGAP2-AS1 silencing,erastin-treated lung cancer cells showed a remarkable decrease inGSH levels.These results indicated that AGAP2-AS1 enhanced the stabilization of SLC7A11 mRNA via Recombinant Insulin Like Growth Factor Binding Protein 2(IGF BP2).Patients with elevated AGAP2-AS1 had considerably worse outcomes.Down-regulating AGAP2-AS1 was able to repress lung cancer cell growth and induce greater Erastin-mediated ferroptosis.Lungcancer cells treated with Erastin exhibited a remarkable decrease inglutathione(GSH)levels.The mechanical findingsindicated that AGAP2-AS1 enhanced the stabilization of SLC7A11 mRNA via the IGF2BP2.Conclusion We identified a novel effect of AGAP2-AS1 on TNM staging and the prognosis of patientswith lungcancer by modulating SLC7A11 mRNA stability and ferroptosis.展开更多
The primary function of terminators is to terminate transcription in gene expression.Although some studies have suggested that terminators also contribute positively to upstream gene expression,the extent and underlyi...The primary function of terminators is to terminate transcription in gene expression.Although some studies have suggested that terminators also contribute positively to upstream gene expression,the extent and underlying mechanism of this effect remain largely unexplored.Here,the correlation between terminating strength and upstream mRNA stability was investigated by constructing a terminator mutation library through randomizing 5 nucleotides,assisted by FlowSeq technology,terminator variants were categorized based on the downstream fluorescence intensity,followed by high-throughput sequencing.To examine the impact of terminators on mRNA stability,the abundance of downstream gene transcripts for each terminator variant was quantified through cDNA sequencing.The results revealed that the transcript abundance controlled by strong terminators was,on average 2.2 times greater than those controlled by weak terminators on average.Moreover,several distinct features could be ascribed to high relative abundance of upstream gene transcript,including a high GC content at the base region of hairpin,and a high AT content in downstream of the U-tract.Additionally,these terminators showed a free energy between28 and22 kcal/mol,and a stem length of 14 nt.Finally,these features ascribed the upstream beneficial terminator were validated across various expression systems.By incorporating the optimal terminator downstream of RSF,GSH and HIS in three different strains,the fermentation productions-NMN SAM and VD13 exhibited a remarkable enhancement of 30%-70%.The findings presented here uncov-ered the terminator characteristics contributed to the upstream mRNA stability,providing guiding principles for gene circuit design.展开更多
Background:Ovarian cancer(OC)is a representative malignancy of the female reproductive system,with a poor prognosis.Long non-coding RNAs(lncRNAs)crucially affect tumor development.This study aimed to identify lncRNAs ...Background:Ovarian cancer(OC)is a representative malignancy of the female reproductive system,with a poor prognosis.Long non-coding RNAs(lncRNAs)crucially affect tumor development.This study aimed to identify lncRNAs that potentially participated in OC.Methods:LncRNA expression in cells and tissues was quantified using reverse transcription-quantitative PCR,while fluorescence in situ hybridization determined their cellular localization.Various in vitro assays,together with a mouse xenograft model,were employed to elucidate the function of CYMP antisense RNA 1(CYMP-AS1)in OC.The molecular mechanisms underlying CYMP-AS1 regulation were investigated through RNA pull-down and immunoprecipitation assays,immunofluorescence staining,western blotting,and mRNA stability assays.Results:This study identified a previously unreported lncRNA,CYMP-AS1,which exhibits increased expression in the cytoplasm of OC tissues and cells.Knockout of CYMP-AS1 reduced the OC cell proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT).CYMP-AS1 directly interacts with heterogeneous nuclear ribonucleoprotein M(hnRNPM),inducing its intracellular translocation and reducing the stability of Axis inhibition protein 2(AXIN2)mRNA.This process ultimately elevated the expression of Wnt/β-catenin signaling pathway-related proteins.Conclusion:This study confirms CYMP-AS1 as a novel biomarker in OC progression and suggests that the CYMP-AS1/hnRNPM/AXIN2 axis may offer an innovative strategy for OC treatment.展开更多
Ectothermic organisms may expand their thermal tolerance by producing multiple protein isoforms with differing thermal sensitivities.While such isoforms commonly originate from allelic variation at a single locus(allo...Ectothermic organisms may expand their thermal tolerance by producing multiple protein isoforms with differing thermal sensitivities.While such isoforms commonly originate from allelic variation at a single locus(allozymes)or from gene duplication that gives rise to paralogs with distinct thermal responses,this study investigated mRNA editing as an alternative,post-transcriptional mechanism for generating mRNA variants.Cytosolic malate dehydrogenase(cMDH)was examined in foot tissue of two congeners of the marine mussel genus Mytilus,which occupy different thermal environments.Multiple editing events were detected within the mRNA coding region in both species.Editing sites were species-specific,with no shared positions identified.In M.coruscus,editing occurred at 117,123,135,190,195,204,279,and 444,while in M.galloprovincialis,editing was detected at 216 and 597.Each species exhibited multiple edited mRNA variants,and these isoforms were associated with differential protein expression.These findings suggest that mRNA editing may contribute an additional layer of molecular variation.The generation of diverse mRNA isoforms from a single DNA coding sequence may enhance enzymatic flexibility across temperature ranges,supporting eurythermal physiological performance and mitigating thermal stress.Moreover,the presence of multiple edited transcripts within individual organisms raises important caveats about the limitations of approaches that deduce amino acid sequences or estimate adaptive variation solely from genomic data.展开更多
BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a cr...BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury.The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1(NIPSNAP1)is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.AIM To clarify the protective mechanism of NIPSNAP1 against hepatic I/R,with a focus on mitophagy and mitochondrial dynamics,as well as the potential mechanism by which n6-methyladenosine(m6A)modification regulates NIPSNAP1.METHODS Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R.HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.RESULTS We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2(IGF2BP2)expression in vivo and in vitro.NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics;in contrast,NIPSNAP1 overexpression resulted in the opposite effects.Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1,thereby regulating its mRNA stability.CONCLUSION NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis,serving as a novel target of the m6A reader IGF2BP2.Therefore,targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.展开更多
Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferropto...Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy.However,the molecular mechanisms underlying ferroptosis resistance in tumor cells remain unknown.Zinc-finger estrogen receptor interaction clone 6(ZER6)consists of two isoforms with distinct N-termini,p52-ZER6 and p71-ZER6.ZER6 is upregulated in tumors and promotes tumorigenic potential;however,whether ZER6 is involved in tumor cell ferroptosis resistance remains unknown.Herein,we identified p52-ZER6 as a novel regulator of tumor cell ferroptosis resistance.p52-ZER6 promotes the transcriptional activity of DAZAP1,an RNA-binding protein.DAZAP1,in turn,enhances the stability of SLC7A11 mRNA by binding to its 30-UTR region,thereby increasing SLC7A11 expression and cellular glutathione levels.This subsequently reduces lipid peroxide accumulation and enhances tumor cell ferroptosis resistance,eventually promoting tumorigenic potential.These findings reveal a new function of p52-ZER6 in regulating SLC7A11 mRNA stability via DAZAP1,ultimately leading to ferroptosis resistance and tumorigenic potential.Additionally,we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.展开更多
Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, trans...Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.展开更多
Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective t...Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.展开更多
N6-Methyladenosine(m6A)modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes.Previous studies have indicated the invol...N6-Methyladenosine(m6A)modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes.Previous studies have indicated the involvement of m6A modification in various tissue regeneration processes,including liver regeneration.Vir-like m6A methyltransferase associated protein(VIRMA)is an m6A methyltransferase with robust methylation capability.However,its role in liver regeneration remains poorly understood.In this study,we generated liver-specific Virma knockout mice using the Cre-loxP system and investigated the biological functions of VIRMA in liver regeneration using both the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy(ALPPS)mouse model and the carbon tetrachloride(CCl4)mouse model.The expression level of VIRMA was rapidly up-regulated after ALPPS surgery and gradually down-regulated during liver repair.Virma deficiency significantly impaired liver regeneration capacity and disrupted cell cycle progression.Methylated RNA immunoprecipitation sequencing(MeRIP-seq)analysis revealed that Shq1 is an effective downstream target of VIRMA-mediated m6A modification.The upregulation of Shq1 enhanced the proliferation ability of cells,which was attenuated by the specific AKT inhibitor ipatasertib.Supplementation of Shq1 in vivo alleviated the liver cell proliferation inhibition caused by Virma deficiency.Furthermore,the m6A-binding protein heterogeneous nuclear ribonucleoprotein a2b1(HNRNPA2B1)enhanced the mRNA stability of Shq1.Mechanistically,Virma deficiency resulted in decreased m6A modification on Shq1 mRNA,leading to reduced binding ability of m6A-binding protein HNRNPA2B1 with Shq1,thereby decreasing the mRNA stability of Shq1 and reducing its protein expression level.Downregulation of Shq1 inhibited the PI3K/AKT pathway,thereby suppressing cell proliferation and cell cycle progression,ultimately impeding liver regeneration.In summary,our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification,providing valuable insights into the epigenetic regulation during liver regeneration.展开更多
Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer develop...Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.展开更多
Foxtail millet(Setaria italica),a vital drought-resistant crop,plays a significant role in ensuring food and nutritional security.However,its drought resistance mechanism is not fully understood.N6-methyladenosine(m^(...Foxtail millet(Setaria italica),a vital drought-resistant crop,plays a significant role in ensuring food and nutritional security.However,its drought resistance mechanism is not fully understood.N6-methyladenosine(m^(6)A)modification of RNA,a prevalent epi-transcriptomic modification in eukaryotes,provides a binding site for m^(6)A readers and affects plant growth and stress responses by regulating RNA metabolism.In this study,we unveiled that the YT521-B homology(YTH)family gene SiYTH1 positively regulated the drought tolerance of foxtail millet.Notably,the siyth1 mutant exhibited reduced stomatal closure and augmented accumulation of excessive H_(2)O_(2)under drought stress.Further investigations demonstrated that SiYTH1 positively regulated the transcripts harboring m^(6)A modification related to stomatal closure and reactive oxygen species(ROS)scavenging under drought stress.SiYTH1 was uniformly distributed in the cytoplasm of SiYTH1-GFP transgenic foxtail millet.It formed dynamic liquid-like SiYTH1 cytosol condensates in response to drought stress.Moreover,the cytoplasmic protein SiYTH1 was identified as a distinct m^(6)A reader,facilitating the stabilization of its directly bound SiARDP and ROS scavenging-related transcripts under drought stress.Furthermore,natural variation analysis revealed SiYTH1AGTG as the dominant allele responsible for drought tolerance in foxtail millet.Collectively,this study provides novel insights into the intricate mechanism of m^(6)A reader-mediated drought tolerance and presents a valuable genetic resource for improving drought tolerance in foxtail millet breeding.展开更多
Long non-coding RNAs(lnc RNAs) are widely involved in a variety of biological processes, including epithelial-mesenchymal transition(EMT). In the current study, we found that lnc RNA small nucleolar RNA host gene 8(SN...Long non-coding RNAs(lnc RNAs) are widely involved in a variety of biological processes, including epithelial-mesenchymal transition(EMT). In the current study, we found that lnc RNA small nucleolar RNA host gene 8(SNHG8) was tightly correlated with EMT-associated gene signatures, and was down-regulated by Zinc finger E-box-binding homeobox 1(ZEB1) during EMT progress. Functionally, knockdown of SNHG8 induced EMT in epithelial cells, through destabilizing the CDH1 m RNA dependent on a 17-nucleotide sequence shared by SNHG8 and CDH1. In addition, analysis with public database showed that SNHG8 tended to be down-regulated in different cancer types and the lower expression of SNHG8 predicted poorer prognosis.Taken together, our study reports a ZEB1-repressed lnc RNA SNHG8 which is important for stabilizing CDH1 m RNA, thereby maintaining the epithelial status of epithelial cells.展开更多
Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.Here,we found that non-small cell lung cance...Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.Here,we found that non-small cell lung cancer(NSCLC)patients with higher plasma mevalonate response better to antiPD-(L)1 therapy,as indicated by prolonged progression-free survival and overall survival.Plasma mevalonate levels were positively correlated with programmed death ligand-1(PD-L1)expression in tumor tissues.In NSCLC cell lines and patient-derived cells,supplementation of mevalonate significantly upregulated the expression of PD-L1,whereas deprivation of mevalonate reduced PD-L1 expression.Mevalonate increased CD274 mRNA level but did not affect CD274 transcription.Further,we confirmed that mevalonate improved CD274 mRNA stability.Mevalonate promoted the affinity of the AU-rich elementbinding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA.By in vivo study,we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1,increased the infiltration of CD8^(+)T cells,and improved cytotoxic function of T cells.Collectively,our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody,and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.展开更多
An enormous amount of long non-coding RNAs（lnc RNAs） transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is the residence and the site of action for many ln...An enormous amount of long non-coding RNAs（lnc RNAs） transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is the residence and the site of action for many lncRNAs. The cytoplasmic lncRNAs play indispensable roles with multiple molecular mechanisms in animal and human cells. In this review, we mainly talk about functions and the underlying mechanisms of lncRNAs in the cytoplasm. We highlight relatively well-studied examples of cytoplasmic lncRNAs for their roles in modulating mRNA stability,regulating m RNA translation, serving as competing endogenous RNAs, functioning as precursors of microRNAs, and mediating protein modifications. We also elaborate the perspectives of cytoplasmic lncRNA studies.展开更多
Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reas...Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.展开更多
Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is preci...Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is precisely regulated by an intricate network that involves transcription levels,signal transduction,and various epigenetic modifications.In recent years,research on posttranscriptional levels in erythropoiesis has expanded significantly.The dynamic regulation of splicing transitions is responsible for changes in protein isoform expression that add new functions beneficial for erythropoiesis.RNA-binding proteins adapt the translation of transcripts to the protein requirements of the cell,yielding mRNA with dynamic translation efficiency.Noncoding RNAs,such as microRNAs and lncRNAs,are indispensable for changing the translational efficiency and/or stability of targeted mRNAs to maintain the normal expression of genes related to erythropoiesis.N6-methyladenosine-dependent regulation of mRNA translation plays an important role in maintaining the expression programs of erythroid-related genes and promoting erythroid lineage determination.This review aims to describe our current understanding of the role of post-transcriptional regulation in erythropoiesis and erythroid-associated diseases,and to shed light on the physiological and pathological implications of the post-transcriptional regulation machinery in erythropoiesis.These may help to further enrich our understanding of the regulatory network of erythropoiesis and provide new strategies for the diagnosis and treatment of erythroid-related diseases.展开更多
基金Project supported by the Talented Scientist Program from South China Agricultural University (No.4600-K14013)the National Natural Science Foundation of China (No.81301901)
文摘Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA processing, and mRNA stability during RNA processing and translation. RNAs, especially mRNAs, are relatively vulnerable molecules in living cells for ribonucleases （RNases）. The maintenance of quality and quantity of transcripts is a key issue for many biological processes. Extensive studies draw the conclusion that the stability of RNAs is dedicated-regulated, occurring co- and post-transcriptionally, and translation-coupled as well, either in the nucleus or cytoplasm. Recently, RNA stability in the nucleus has aroused much research interest, especially the stability of newly-made transcripts. In this article, we summarize recent progresses on mRNA stability in the nucleus, especially focusing on quality control of newly-made RNA by RNA polymerase Ⅱ in eukaryotes.
基金Supported by the Wuhan Municipal Health Commission Medical Research Project-Youth Project(No.WZ20Q04).
文摘Objective The initiation and progression of lung carcinomas are critically regulated by long non-coding RNAs(lncRNAs).However,the role of lncRNAs in the pathways causing lung cancer remains unknown.Methods Cell morphology was regularly observed using an inverted phase-contrast microscope.Cell viability was assessed using CCK-8 according to the manufacturer’s instructions.Total RNA was retrotranscribed from each specimen using the RNAiso Plus Kit.The RT-PCR data were calculated using the Ct approach for comparison.Flow cytometric analyses were prepared by Click-iT™Plus TUNEL Assay for In Situ apoptosis detection,with Alexa Fluor^(TM)594 dye,as instructed.RNA immunoprecipitation assays were used to determine RNA concentration.Results Activated natural killer cells repeat and PH domain-containing protein 2 antisense RNA 1(AGAP2-AS1)levels in cancerous tissues were significantly correlated with cancerous tumor node metastasis(TNM)stage,with cancerous AGAP2-AS1 levels being higher in cancerous tissues than healthy tissues.Patients withelevated AGAP2-AS1 levels had considerably worse outcomes than those with reduced AGAP2-AS1 levels,regardless of the progression-free or overall survival.Functionally,AGAP2-AS1 downregulation represseslung cancer cell growth.AGAP2-AS1 elimination induces erastin-mediated ferroptosis in lung cancer cells.However,the ferritin inhibitor FERSINT-1 negated this result,whereas ERASTIN induced lung cancer cellmortality.After AGAP2-AS1 silencing,erastin-treated lung cancer cells showed a remarkable decrease inGSH levels.These results indicated that AGAP2-AS1 enhanced the stabilization of SLC7A11 mRNA via Recombinant Insulin Like Growth Factor Binding Protein 2(IGF BP2).Patients with elevated AGAP2-AS1 had considerably worse outcomes.Down-regulating AGAP2-AS1 was able to repress lung cancer cell growth and induce greater Erastin-mediated ferroptosis.Lungcancer cells treated with Erastin exhibited a remarkable decrease inglutathione(GSH)levels.The mechanical findingsindicated that AGAP2-AS1 enhanced the stabilization of SLC7A11 mRNA via the IGF2BP2.Conclusion We identified a novel effect of AGAP2-AS1 on TNM staging and the prognosis of patientswith lungcancer by modulating SLC7A11 mRNA stability and ferroptosis.
基金supported by National Natural Science Foundation of China[32171421].
文摘The primary function of terminators is to terminate transcription in gene expression.Although some studies have suggested that terminators also contribute positively to upstream gene expression,the extent and underlying mechanism of this effect remain largely unexplored.Here,the correlation between terminating strength and upstream mRNA stability was investigated by constructing a terminator mutation library through randomizing 5 nucleotides,assisted by FlowSeq technology,terminator variants were categorized based on the downstream fluorescence intensity,followed by high-throughput sequencing.To examine the impact of terminators on mRNA stability,the abundance of downstream gene transcripts for each terminator variant was quantified through cDNA sequencing.The results revealed that the transcript abundance controlled by strong terminators was,on average 2.2 times greater than those controlled by weak terminators on average.Moreover,several distinct features could be ascribed to high relative abundance of upstream gene transcript,including a high GC content at the base region of hairpin,and a high AT content in downstream of the U-tract.Additionally,these terminators showed a free energy between28 and22 kcal/mol,and a stem length of 14 nt.Finally,these features ascribed the upstream beneficial terminator were validated across various expression systems.By incorporating the optimal terminator downstream of RSF,GSH and HIS in three different strains,the fermentation productions-NMN SAM and VD13 exhibited a remarkable enhancement of 30%-70%.The findings presented here uncov-ered the terminator characteristics contributed to the upstream mRNA stability,providing guiding principles for gene circuit design.
基金funded by the National Natural Science Foundation of China(No.8207286).
文摘Background:Ovarian cancer(OC)is a representative malignancy of the female reproductive system,with a poor prognosis.Long non-coding RNAs(lncRNAs)crucially affect tumor development.This study aimed to identify lncRNAs that potentially participated in OC.Methods:LncRNA expression in cells and tissues was quantified using reverse transcription-quantitative PCR,while fluorescence in situ hybridization determined their cellular localization.Various in vitro assays,together with a mouse xenograft model,were employed to elucidate the function of CYMP antisense RNA 1(CYMP-AS1)in OC.The molecular mechanisms underlying CYMP-AS1 regulation were investigated through RNA pull-down and immunoprecipitation assays,immunofluorescence staining,western blotting,and mRNA stability assays.Results:This study identified a previously unreported lncRNA,CYMP-AS1,which exhibits increased expression in the cytoplasm of OC tissues and cells.Knockout of CYMP-AS1 reduced the OC cell proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT).CYMP-AS1 directly interacts with heterogeneous nuclear ribonucleoprotein M(hnRNPM),inducing its intracellular translocation and reducing the stability of Axis inhibition protein 2(AXIN2)mRNA.This process ultimately elevated the expression of Wnt/β-catenin signaling pathway-related proteins.Conclusion:This study confirms CYMP-AS1 as a novel biomarker in OC progression and suggests that the CYMP-AS1/hnRNPM/AXIN2 axis may offer an innovative strategy for OC treatment.
基金supported by the National Key Research and Development Program of China(2022-24)National Natural Science Foundation of China(42025604,42376102)Fundamental Research Funds for the Central Universities。
文摘Ectothermic organisms may expand their thermal tolerance by producing multiple protein isoforms with differing thermal sensitivities.While such isoforms commonly originate from allelic variation at a single locus(allozymes)or from gene duplication that gives rise to paralogs with distinct thermal responses,this study investigated mRNA editing as an alternative,post-transcriptional mechanism for generating mRNA variants.Cytosolic malate dehydrogenase(cMDH)was examined in foot tissue of two congeners of the marine mussel genus Mytilus,which occupy different thermal environments.Multiple editing events were detected within the mRNA coding region in both species.Editing sites were species-specific,with no shared positions identified.In M.coruscus,editing occurred at 117,123,135,190,195,204,279,and 444,while in M.galloprovincialis,editing was detected at 216 and 597.Each species exhibited multiple edited mRNA variants,and these isoforms were associated with differential protein expression.These findings suggest that mRNA editing may contribute an additional layer of molecular variation.The generation of diverse mRNA isoforms from a single DNA coding sequence may enhance enzymatic flexibility across temperature ranges,supporting eurythermal physiological performance and mitigating thermal stress.Moreover,the presence of multiple edited transcripts within individual organisms raises important caveats about the limitations of approaches that deduce amino acid sequences or estimate adaptive variation solely from genomic data.
基金Supported by the National Natural Science Foundation of China,No.82200658.
文摘BACKGROUND Hepatic ischemia-reperfusion(I/R)injury related to liver transplantation and hepatic resection remains a challenge in clinical practice.Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury.The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1(NIPSNAP1)is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.AIM To clarify the protective mechanism of NIPSNAP1 against hepatic I/R,with a focus on mitophagy and mitochondrial dynamics,as well as the potential mechanism by which n6-methyladenosine(m6A)modification regulates NIPSNAP1.METHODS Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R.HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.RESULTS We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2(IGF2BP2)expression in vivo and in vitro.NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics;in contrast,NIPSNAP1 overexpression resulted in the opposite effects.Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1,thereby regulating its mRNA stability.CONCLUSION NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis,serving as a novel target of the m6A reader IGF2BP2.Therefore,targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.
基金supported by grants from the National Natural Science Foundation of China(82372655,82173029,32270778,and 32070715)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0611 and CSTB2022NSCQ-MSX0612,China).
文摘Resistance to ferroptosis,a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis,is closely related to tumorigenesis and tumor drug resistance;therefore,targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy.However,the molecular mechanisms underlying ferroptosis resistance in tumor cells remain unknown.Zinc-finger estrogen receptor interaction clone 6(ZER6)consists of two isoforms with distinct N-termini,p52-ZER6 and p71-ZER6.ZER6 is upregulated in tumors and promotes tumorigenic potential;however,whether ZER6 is involved in tumor cell ferroptosis resistance remains unknown.Herein,we identified p52-ZER6 as a novel regulator of tumor cell ferroptosis resistance.p52-ZER6 promotes the transcriptional activity of DAZAP1,an RNA-binding protein.DAZAP1,in turn,enhances the stability of SLC7A11 mRNA by binding to its 30-UTR region,thereby increasing SLC7A11 expression and cellular glutathione levels.This subsequently reduces lipid peroxide accumulation and enhances tumor cell ferroptosis resistance,eventually promoting tumorigenic potential.These findings reveal a new function of p52-ZER6 in regulating SLC7A11 mRNA stability via DAZAP1,ultimately leading to ferroptosis resistance and tumorigenic potential.Additionally,we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.
文摘Vascular endothelial growth factor （VEGF） is a potent secreted mitogen critical for physiologic and tumor angiogenesis. Regulation of VEGF occurs at several levels, including transcription, mRNA stabilization, translation, and differential cellular localization of various isoforms. Recent advances in our understanding of post-transcriptional regulation of VEGF include identification of the stabilizing mRNA binding protein, HuR, and the discovery of internal ribosomal entry sites in the 5＇UTR of the VEGF mRNA. Monoclonal anti-VEGF antibody was recently approved for use in humans, but suffers from the need for high systemic doses. RNA interference （RNAi） technology is being used in vitro and in animal models with promising results. Here, we review the literature on post-transcriptional regulation of VEGF and describe recent progress in targeting these mechanisms for therapeutic benefit.
基金funded by National Natural Science Foundation of China(grant numbers:81872335,82303891 and 82303119)The Central Plains Science and Technology Innovation Leading Talents(No.224200510015,China)+1 种基金Key scientific research project plan of colleges and universities in Henan Province(grant number:24A310025,China)Science and Technology Project of Henan Province(No.242102310414,China).
文摘Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.
基金supported by grants from the National multidisciplinary collaborative diagnosis and treatment capacity building project for major diseases(TJZ202104,China)the Natural Science Foundation of China(82270643,82070644,82170621 and 82370645)+3 种基金the Science and Technology Major Program of Sichuan Province(2022ZDZX0019,China)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University,China(ZYJC18008,ZYGD22006)Luzhou Municipal People's Government-Southwest Medical University Science and Technology Strategic Cooperation Project,China(2024LZXNYDJ045)the Medical Science and Technology Development Project of Southwest Medical University,China(24297).
文摘N6-Methyladenosine(m6A)modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes.Previous studies have indicated the involvement of m6A modification in various tissue regeneration processes,including liver regeneration.Vir-like m6A methyltransferase associated protein(VIRMA)is an m6A methyltransferase with robust methylation capability.However,its role in liver regeneration remains poorly understood.In this study,we generated liver-specific Virma knockout mice using the Cre-loxP system and investigated the biological functions of VIRMA in liver regeneration using both the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy(ALPPS)mouse model and the carbon tetrachloride(CCl4)mouse model.The expression level of VIRMA was rapidly up-regulated after ALPPS surgery and gradually down-regulated during liver repair.Virma deficiency significantly impaired liver regeneration capacity and disrupted cell cycle progression.Methylated RNA immunoprecipitation sequencing(MeRIP-seq)analysis revealed that Shq1 is an effective downstream target of VIRMA-mediated m6A modification.The upregulation of Shq1 enhanced the proliferation ability of cells,which was attenuated by the specific AKT inhibitor ipatasertib.Supplementation of Shq1 in vivo alleviated the liver cell proliferation inhibition caused by Virma deficiency.Furthermore,the m6A-binding protein heterogeneous nuclear ribonucleoprotein a2b1(HNRNPA2B1)enhanced the mRNA stability of Shq1.Mechanistically,Virma deficiency resulted in decreased m6A modification on Shq1 mRNA,leading to reduced binding ability of m6A-binding protein HNRNPA2B1 with Shq1,thereby decreasing the mRNA stability of Shq1 and reducing its protein expression level.Downregulation of Shq1 inhibited the PI3K/AKT pathway,thereby suppressing cell proliferation and cell cycle progression,ultimately impeding liver regeneration.In summary,our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification,providing valuable insights into the epigenetic regulation during liver regeneration.
基金National Natural Science Foundation of China,Grant/Award Numbers:81902386,81972869,82002479The Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211065,BK20200179+2 种基金China Postdoctoral Science Foundation,Grant/Award Number:2021M700547Youth Talent Science and Technology Project of Changzhou Health Commission,Grant/Award Number:QN202103The open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University,China,Grant/Award Number:KF-202203。
文摘Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.
基金This work was supported by the National Key R&D Program of China(2023YFD1200700/2023YFD1200702/2018YFD1000700/2018YFD1000704).
文摘Foxtail millet(Setaria italica),a vital drought-resistant crop,plays a significant role in ensuring food and nutritional security.However,its drought resistance mechanism is not fully understood.N6-methyladenosine(m^(6)A)modification of RNA,a prevalent epi-transcriptomic modification in eukaryotes,provides a binding site for m^(6)A readers and affects plant growth and stress responses by regulating RNA metabolism.In this study,we unveiled that the YT521-B homology(YTH)family gene SiYTH1 positively regulated the drought tolerance of foxtail millet.Notably,the siyth1 mutant exhibited reduced stomatal closure and augmented accumulation of excessive H_(2)O_(2)under drought stress.Further investigations demonstrated that SiYTH1 positively regulated the transcripts harboring m^(6)A modification related to stomatal closure and reactive oxygen species(ROS)scavenging under drought stress.SiYTH1 was uniformly distributed in the cytoplasm of SiYTH1-GFP transgenic foxtail millet.It formed dynamic liquid-like SiYTH1 cytosol condensates in response to drought stress.Moreover,the cytoplasmic protein SiYTH1 was identified as a distinct m^(6)A reader,facilitating the stabilization of its directly bound SiARDP and ROS scavenging-related transcripts under drought stress.Furthermore,natural variation analysis revealed SiYTH1AGTG as the dominant allele responsible for drought tolerance in foxtail millet.Collectively,this study provides novel insights into the intricate mechanism of m^(6)A reader-mediated drought tolerance and presents a valuable genetic resource for improving drought tolerance in foxtail millet breeding.
基金This work was supported by the National Natural Science Foundation of China(82022053,81830091,91853206,and 81972583)the National Key Research and Development Program of China(2020YFA0803403)+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-051)the Fundamental Research Funds for the Central Universities.
文摘Long non-coding RNAs(lnc RNAs) are widely involved in a variety of biological processes, including epithelial-mesenchymal transition(EMT). In the current study, we found that lnc RNA small nucleolar RNA host gene 8(SNHG8) was tightly correlated with EMT-associated gene signatures, and was down-regulated by Zinc finger E-box-binding homeobox 1(ZEB1) during EMT progress. Functionally, knockdown of SNHG8 induced EMT in epithelial cells, through destabilizing the CDH1 m RNA dependent on a 17-nucleotide sequence shared by SNHG8 and CDH1. In addition, analysis with public database showed that SNHG8 tended to be down-regulated in different cancer types and the lower expression of SNHG8 predicted poorer prognosis.Taken together, our study reports a ZEB1-repressed lnc RNA SNHG8 which is important for stabilizing CDH1 m RNA, thereby maintaining the epithelial status of epithelial cells.
基金supported by National Natural Science Foundation of China(No.81930102 to Bo Yang,No.82104196 to Xi Chen,No.82273949 to Ling Ding)Key R&D Program of Zhejiang(No.2022C03143 to Qinjie Weng,China)。
文摘Mevalonate metabolism plays an important role in regulating tumor growth and progression;however,its role in immune evasion and immune checkpoint modulation remains unclear.Here,we found that non-small cell lung cancer(NSCLC)patients with higher plasma mevalonate response better to antiPD-(L)1 therapy,as indicated by prolonged progression-free survival and overall survival.Plasma mevalonate levels were positively correlated with programmed death ligand-1(PD-L1)expression in tumor tissues.In NSCLC cell lines and patient-derived cells,supplementation of mevalonate significantly upregulated the expression of PD-L1,whereas deprivation of mevalonate reduced PD-L1 expression.Mevalonate increased CD274 mRNA level but did not affect CD274 transcription.Further,we confirmed that mevalonate improved CD274 mRNA stability.Mevalonate promoted the affinity of the AU-rich elementbinding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA.By in vivo study,we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1,increased the infiltration of CD8^(+)T cells,and improved cytotoxic function of T cells.Collectively,our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody,and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.
基金supported by the National Basic Research Program of China (973 Program Grant No. 2015CB943000)+1 种基金the National Natural Science Foundation of China (Grant Nos. 91519333 and 31471225)the Fundamental Research Funds for the Central Universities (Grant No. WK2070000034)
文摘An enormous amount of long non-coding RNAs（lnc RNAs） transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is the residence and the site of action for many lncRNAs. The cytoplasmic lncRNAs play indispensable roles with multiple molecular mechanisms in animal and human cells. In this review, we mainly talk about functions and the underlying mechanisms of lncRNAs in the cytoplasm. We highlight relatively well-studied examples of cytoplasmic lncRNAs for their roles in modulating mRNA stability,regulating m RNA translation, serving as competing endogenous RNAs, functioning as precursors of microRNAs, and mediating protein modifications. We also elaborate the perspectives of cytoplasmic lncRNA studies.
基金Science Fund for Creative Research Groups of the National Natural Science Foundation of China,Grant/Award Number:81521004National Natural Science Foundation of China,Grant/Award Numbers:81922061,82172992,81903391,81702266+2 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers,Chinese Academy of Medical Sciences,Grant/Award Number:2019RU038Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211253,BK20190148Postgraduate Research&Practice Innovation Program of Jiangsu Province,Grant/Award Number:KYCX18_0195。
文摘Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.
基金supported by grants from the National Natural Science Foundation of China(Grant numbers 81920108004 and 82270127)the Fundamental Research Funds of the Central Universities of Central South University(Grant number 2021zzts0562)the Fundamental Research Funds for the Scientific Research Innovation Project of Hunan Province(Grant number CX20210182).
文摘Erythropoiesis is a complex,precise,and lifelong process that is essential for maintaining normal body functions.Its strict regulation is necessary to prevent a variety of blood diseases.Normal erythropoiesis is precisely regulated by an intricate network that involves transcription levels,signal transduction,and various epigenetic modifications.In recent years,research on posttranscriptional levels in erythropoiesis has expanded significantly.The dynamic regulation of splicing transitions is responsible for changes in protein isoform expression that add new functions beneficial for erythropoiesis.RNA-binding proteins adapt the translation of transcripts to the protein requirements of the cell,yielding mRNA with dynamic translation efficiency.Noncoding RNAs,such as microRNAs and lncRNAs,are indispensable for changing the translational efficiency and/or stability of targeted mRNAs to maintain the normal expression of genes related to erythropoiesis.N6-methyladenosine-dependent regulation of mRNA translation plays an important role in maintaining the expression programs of erythroid-related genes and promoting erythroid lineage determination.This review aims to describe our current understanding of the role of post-transcriptional regulation in erythropoiesis and erythroid-associated diseases,and to shed light on the physiological and pathological implications of the post-transcriptional regulation machinery in erythropoiesis.These may help to further enrich our understanding of the regulatory network of erythropoiesis and provide new strategies for the diagnosis and treatment of erythroid-related diseases.
