The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By ...The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder(ASD),bipolar disorder(BD),schizophrenia(SCZ),and controls,we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders.Approximately 30%of the expression variability was attributed to post-transcriptional dysregulation.Interestingly,mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD,leading to the inhibition of neurogenesis and neural differentiation,while they were upregulated in ASD,resulting in enhanced activity of apoptosis.These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders.An RNA-binding protein,ELAVL3,was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders.To validate this,we knocked down its expression in cerebral organoids.Not only did the differentially expressed genes in ELAVL3 knockdown cover a considerable proportion of predicted targets in the three disorders,but we also found that neurogenesis was significantly affected,given the diminished proliferation and consequently reduced size of the organoids.The present study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.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
Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells ...Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.展开更多
There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral li...There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral lifecycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing antiviral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regulatory element identified 20 years ago promotes nucleocytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5’ end of the polycistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regulate gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.展开更多
While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from th...While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.展开更多
AIM To determine the association of human antigen R(HuR) and inhibitors of apoptosis proteins(IAP1, IAP2) and prognosis in pancreatic cancer.METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreat...AIM To determine the association of human antigen R(HuR) and inhibitors of apoptosis proteins(IAP1, IAP2) and prognosis in pancreatic cancer.METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma(PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction(RT-PCR), western blot analysis was carried out.RESULTS RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas(P < 0.05). Expression of IAP1 was positively strongly correlated with HuR expression(P < 0.05, r = 0.783). Western blot analysis confirmed RTPCR results. High IAP1 expression, tumor resection status, T stage, lymph-node metastases, tumor differentiation grade, perineural and lymphatic invasion were identified as significant factors for shorter survival in PDAC patients(P < 0.05).Immunohistological analysis showed that HuR was mainly expressed in the ductal cancer cell's nucleus and less so in cytoplasm. RNA immunoprecipitation analysis confirmed IAP1 and IAP2 post-transcriptional regulation by HuR protein. Following siHuR transfection, IAP1 mRNA and protein levels were decreased, however IAP2 expression levels were increased.CONCLUSION HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.展开更多
Background It is still unclear whether viral genetic variability influences response to interferon(IFN) α treatment Recent reports suggest that IFN α effects may be associated with hepatitis B virus(HBV) post ...Background It is still unclear whether viral genetic variability influences response to interferon(IFN) α treatment Recent reports suggest that IFN α effects may be associated with hepatitis B virus(HBV) post transcriptional regulation This study was designed to explore the heterogeneity of HBV post transcriptional regulatory elements (HPRE) and the relationship between the diversity of HPRE and the response to IFN α treatment Methods The HPRE sequences from 31 Chinese patients infected with HBV were determined by directly sequencing of polymerase chain reaction (PCR) product, and comparing them to those from Caucasian patients Subsequently, eukaryotic expression vectors containing HPRE at various points were constructed and transfected into HepG2 cells, which were then exposed to recombinant human cytokines Results The T to C point mutation at nt 1504 and the C to T (G) at nt 1508 in HPRE were found in 21 and 19 patients with chronic hepatitis B, respectively; the C to T point mutation at nt 1509 was found in 17 patients These point mutations did not exist in the HPRE of the Caucasian patients The activity of the CAT gene obviously increased in the case of T to C point mutation at nt 1504, but did not change in the case of the C to T (G) mutations at nt 1508 and 1509 The activity of the CAT gene at these point mutations of HPRE could be inhibited by IFN α/γ and tumor necrosis factor (TNF) α except for the point mutations at nt 1508 of HPRE which may escape the suppression role of IFN α on HPRE Conclusions There are point mutations between the HPRE of Chinese and Caucasian HBV patients, which might be correlated with response to IFN α The variation of HPRE might affect the function of HPRE and influence the regulative function of IFN α other than that of IFN γ or TNF α on HPRE展开更多
In plants, post-transcriptional gene silencing(PTGS) protects the genome from foreign genes and restricts the expression of certain endogenous genes for proper development. Here, we review the recent progress about ho...In plants, post-transcriptional gene silencing(PTGS) protects the genome from foreign genes and restricts the expression of certain endogenous genes for proper development. Here, we review the recent progress about how the unwanted PTGS is avoided in plants. As a decision-making step of PTGS, aberrant transcripts from most endogenous coding genes are strictly sorted to the bidirectional RNA decay pathways in cytoplasm but not to the short interference RNA(si RNA)-mediated PTGS, with the exception of a few development-relevant endogenous si RNA-producing genes. We also discuss a finely balanced PTGS threshold model that plants fully take advantage of the power of PTGS without self-harm.展开更多
In Papilionoideae legume, Lotusjaponicus, the development of dorsal-ventral （DV） asymmetric flowers is mainly controlled by two TB1/CYCLOIDEA/PCF （TCP） genes, SQUARED STANDARD （SQU） and KEELED WINGS IN LOTUS （...In Papilionoideae legume, Lotusjaponicus, the development of dorsal-ventral （DV） asymmetric flowers is mainly controlled by two TB1/CYCLOIDEA/PCF （TCP） genes, SQUARED STANDARD （SQU） and KEELED WINGS IN LOTUS （KEW）, which determine dorsal and lateral identities, respectively. However, the molecular basis of how these two highly homologous genes orchestrate their diverse functions remains unclear. Here, we analyzed their expression levels, and investigated the transcriptional activities of SQUand KEW. We demonstrated that SQU possesses both activation and repression activities, while KEW acts only as an activator. They form homo- and heterodimers, and then collaboraUvely regulate their expression at the transcription level. Furthermore, we identified two types of post-transcriptional modifications, phosphor- ylation and ATP/GTP binding, both of which could affect their transcriptional activities. Mutations in ATP/ GTP binding motifs of SQU and KEW lead to failure of phosphorylation, and transgenic plants bearing the mutant proteins display defective DV asymmetric flower development, indicating that the two conjugate modifications are essential for their diverse functions. Altogether, SQU and KEW activities are precisely modulated at both transcription and post-transcription levels, which might link DV asymmetric flower development to different physiological status and/or signaling pathways.展开更多
Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transfor...Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.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
Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to r...Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics,for example drug repurposing.To identify potentially repurposable drugs,we employed a systematic approach to mine candidates from U.S.FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients withmild and severe COVID-19(GEO:GSE145926,public data available and accessed on 22 April 2020).We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19.We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a,two chemical inhibitors of glycosylation(a post-translational modification)on the replication of the single-stranded ribonucleic acid(ssRNA)virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators(IFNs and ISGs).In conclusion,we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach,which may have the potential for treating these viral infections and their complications(sepsis).展开更多
Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome ap...Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA （lncRNA）, a heteroge- neous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA （miRNA） pathways, lncRNA has been shown to act as both a source and an inhi- bitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying com- plexes by directing them to specific loci.展开更多
Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions,including impairment of the barrier functions,control of vascular tone,disturbance of proliferative and migra...Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions,including impairment of the barrier functions,control of vascular tone,disturbance of proliferative and migratory capacity of endothelial cells,as well as control of leukocyte trafficking.Endothelial dysfunction is an early step in vascular inflammatory diseases such as atherosclerosis,diabetic vascular complications,sepsis-induced or severe virus infection-induced organ injuries.The expressions of inflammatory cytokines and vascular adhesion molecules induced by various stimuli,such as modified lipids,smoking,advanced glycation end products and bacteria toxin,significantly contribute to the development of endothelial dysfunction.The transcriptional regulation of inflammatory cytokines and vascular adhesion molecules has been well-studied.However,the regulation of those gene expressions at post-transcriptional level is emerging.RNA-binding proteins have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level in microRNA-dependent or independent manners.This review summarizes the latest insights into the roles of RNA-binding proteins in controlling vascular endothelial cell functions and their contribution to the pathogenesis of vascular inflammatory diseases.展开更多
Hematopoiesis represents a meticulously regulated and dynamic biological process.Genetic aberrations affecting blood cells,induced by various factors,frequently give rise to hematological tumors.These instances are of...Hematopoiesis represents a meticulously regulated and dynamic biological process.Genetic aberrations affecting blood cells,induced by various factors,frequently give rise to hematological tumors.These instances are often accompanied by a multitude of abnormal post-transcriptional regulatory events,including RNA alternative splicing,RNA localization,RNA degradation,and storage.Notably,post-transcriptional regulation plays a pivotal role in preserving hematopoietic homeostasis.The DEAD-Box RNA helicase genes emerge as crucial post-transcriptional regulatory factors,intricately involved in sustaining normal hematopoiesis through diverse mechanisms such as RNA alternative splicing,RNA modification,and ribosome assembly.This review consolidates the existing knowledge on the role of DEAD-box RNA helicases in regulating normal hematopoiesis and underscores the pathogenicity of mutant DEADBox RNA helicases in malignant hematopoiesis.Emphasis is placed on elucidating both the positive and negative contributions of DEAD-box RNA helicases within the hematopoietic system.展开更多
RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional ...RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional characterizations,and transcriptomic and population genomic analyses,we revealed that RBP-K(LOC_Os08g23120),RBP-A(LOC_Os11g41890),and RBP-J(LOC_Os10g33230)encode proteins that form an RBP-A-J-K complex that negatively regulates rice yield-related traits.Examinations of the RBP-A-J-K complex indicated RBP-K functions as a relatively non-specific RBP chaperone that enables RBP-A and RBP-J to function normally.Additionally,RBP-J most likely affects GA pathways,resulting in considerable increases in grain and panicle lengths,but decreases in grain width and thickness.In contrast,RBP-A negatively regulates the expression of genes most likely involved in auxin-regulated pathways controlling cell wall elongation and carbohydrate transport,with substantial effects on the rice grain filling process as well as grain length and weight.Evolutionarily,RBP-K is relatively ancient and highly conserved,whereas RBP-J and RBP-A are more diverse.Thus,the RBP-A-J-K complex may represent a typical functional model for many RBPs and protein complexes that function at transcriptional and post-transcriptional levels in plants and animals for increased functional consistency,efficiency,and versatility,as well as increased evolutionary potential.Our results clearly demonstrate the importance of RBP-mediated post-transcriptional regulation for the diversity of complex traits.Furthermore,rice grain yield and quality may be enhanced by introducing various complete or partial loss-of-function mutations to specific RBP genes using clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9 technology and by exploiting desirable natural tri-genic allelic combinations at the loci encoding the components of the RBP-A-J-K complex through marker-assisted selection.展开更多
MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated ce...MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated cell proliferation,tumorigenesis,and ultimately,cancer.Increasing evidences suggested that a large fraction of miRNAs is regulated at the posttranscriptional stage,which impacts on the level and function of miRNAs during cell development and human diseases.Recently,several distinct mechanisms are emerging to regulate the biogenesis,stability and function of miRNAs at post-transcriptional level,such as specific binding to terminal loops of miRNA precursors(primiRNAs or pre-miRNAs)by RNA-binding proteins and 3’-terminal modifications by particular enzymes.Signaling cascades and post-translational modifications of the core components of RNA machinery also take part in the posttranscriptional regulation of miRNAs.展开更多
猪繁殖与呼吸综合征(porcine reproductive and respiratory syndrome,PRRS)是由猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome virus,PRRSV)引起的以猪呼吸系统疾病和母猪繁殖障碍为主要特征的传染病,给全球...猪繁殖与呼吸综合征(porcine reproductive and respiratory syndrome,PRRS)是由猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome virus,PRRSV)引起的以猪呼吸系统疾病和母猪繁殖障碍为主要特征的传染病,给全球养猪业造成了巨大的经济损失。然而,PRRS至今仍没有安全有效的疫苗和药物进行防治。全面深入理解PRRSV生命周期可以为PRRS防控提供新的思路。因此,本文在简述PRRSV生命周期的基础上,重点对病毒侵入、复制与转录、翻译及翻译后修饰、组装等过程的研究进展进行综述,以期为PRRSV致病机制及防控研究提供参考。展开更多
文摘The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of posttranscriptional mechanisms;however,the role of the latter in many diseases remains relatively unknown.By using an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder(ASD),bipolar disorder(BD),schizophrenia(SCZ),and controls,we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic alterations in neuropsychiatric disorders.Approximately 30%of the expression variability was attributed to post-transcriptional dysregulation.Interestingly,mature mRNA levels tended to be post-transcriptionally downregulated in SCZ and BD,leading to the inhibition of neurogenesis and neural differentiation,while they were upregulated in ASD,resulting in enhanced activity of apoptosis.These findings imply contrasting pathologies involving RNA metabolism across neuropsychiatric disorders.An RNA-binding protein,ELAVL3,was predicted to be significantly involved in the disruption of post-transcriptional regulation in all three disorders.To validate this,we knocked down its expression in cerebral organoids.Not only did the differentially expressed genes in ELAVL3 knockdown cover a considerable proportion of predicted targets in the three disorders,but we also found that neurogenesis was significantly affected,given the diminished proliferation and consequently reduced size of the organoids.The present study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new potential therapeutic targets for early intervention.
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supported by Stavros Niarhos FoundationGreek‘Flagship Action for the Study of Neurodegenerative Diseases on the Basis of Precision Medicine’(to DT).
文摘Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action.
基金Supported by Thailand Research Fundthe Commission on Higher Education Fund grant(to Nattanan Panjaworayan T-Thienprasert),No.MRG5680051and NZ Health Research Council Grant 05/195(to Augustine Chen and Chris M Brown)
文摘There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral lifecycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing antiviral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regulatory element identified 20 years ago promotes nucleocytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5’ end of the polycistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regulate gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.
文摘While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.
文摘AIM To determine the association of human antigen R(HuR) and inhibitors of apoptosis proteins(IAP1, IAP2) and prognosis in pancreatic cancer.METHODS Protein and mRNA expression levels of IAP1, IAP2 and HuR in pancreatic ductal adenocarcinoma(PDAC) were compared with normal pancreatic tissue. The correlations among IAP1/IAP2 and HuR as well as their respective correlations with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for survival analysis. Immunoprecipitation assay was performed to demonstrate HuR binding to IAP1, IAP2 mRNA. PANC1 cells were transfected with either anti-HuR siRNA or control siRNA for 72 h and quantitative reverse transcription polymerase chain reaction(RT-PCR), western blot analysis was carried out.RESULTS RT-PCR analysis revealed that HuR, IAP1, IAP2 mRNA expression were accordingly 3.3-fold, 5.5-fold and 8.4 higher in the PDAC when compared to normal pancreas(P < 0.05). Expression of IAP1 was positively strongly correlated with HuR expression(P < 0.05, r = 0.783). Western blot analysis confirmed RTPCR results. High IAP1 expression, tumor resection status, T stage, lymph-node metastases, tumor differentiation grade, perineural and lymphatic invasion were identified as significant factors for shorter survival in PDAC patients(P < 0.05).Immunohistological analysis showed that HuR was mainly expressed in the ductal cancer cell's nucleus and less so in cytoplasm. RNA immunoprecipitation analysis confirmed IAP1 and IAP2 post-transcriptional regulation by HuR protein. Following siHuR transfection, IAP1 mRNA and protein levels were decreased, however IAP2 expression levels were increased.CONCLUSION HuR mediated overexpression of IAP1 significantly correlates with poor outcomes and early progression of pancreatic cancer. Further studies are needed to assess the underlying mechanisms.
文摘Background It is still unclear whether viral genetic variability influences response to interferon(IFN) α treatment Recent reports suggest that IFN α effects may be associated with hepatitis B virus(HBV) post transcriptional regulation This study was designed to explore the heterogeneity of HBV post transcriptional regulatory elements (HPRE) and the relationship between the diversity of HPRE and the response to IFN α treatment Methods The HPRE sequences from 31 Chinese patients infected with HBV were determined by directly sequencing of polymerase chain reaction (PCR) product, and comparing them to those from Caucasian patients Subsequently, eukaryotic expression vectors containing HPRE at various points were constructed and transfected into HepG2 cells, which were then exposed to recombinant human cytokines Results The T to C point mutation at nt 1504 and the C to T (G) at nt 1508 in HPRE were found in 21 and 19 patients with chronic hepatitis B, respectively; the C to T point mutation at nt 1509 was found in 17 patients These point mutations did not exist in the HPRE of the Caucasian patients The activity of the CAT gene obviously increased in the case of T to C point mutation at nt 1504, but did not change in the case of the C to T (G) mutations at nt 1508 and 1509 The activity of the CAT gene at these point mutations of HPRE could be inhibited by IFN α/γ and tumor necrosis factor (TNF) α except for the point mutations at nt 1508 of HPRE which may escape the suppression role of IFN α on HPRE Conclusions There are point mutations between the HPRE of Chinese and Caucasian HBV patients, which might be correlated with response to IFN α The variation of HPRE might affect the function of HPRE and influence the regulative function of IFN α other than that of IFN γ or TNF α on HPRE
基金supported by the National Basic Research Program of China(2012CB910902)the National Natural Science Foundation of China(9121730591017010)to H.G
文摘In plants, post-transcriptional gene silencing(PTGS) protects the genome from foreign genes and restricts the expression of certain endogenous genes for proper development. Here, we review the recent progress about how the unwanted PTGS is avoided in plants. As a decision-making step of PTGS, aberrant transcripts from most endogenous coding genes are strictly sorted to the bidirectional RNA decay pathways in cytoplasm but not to the short interference RNA(si RNA)-mediated PTGS, with the exception of a few development-relevant endogenous si RNA-producing genes. We also discuss a finely balanced PTGS threshold model that plants fully take advantage of the power of PTGS without self-harm.
基金This work was supported by National Natural Science Foundation of China （Grant Noa. 30930009） and Science and Technology Planning Project of Guangdong Province, China （Grant Nos, 2011A020201008）.
文摘In Papilionoideae legume, Lotusjaponicus, the development of dorsal-ventral （DV） asymmetric flowers is mainly controlled by two TB1/CYCLOIDEA/PCF （TCP） genes, SQUARED STANDARD （SQU） and KEELED WINGS IN LOTUS （KEW）, which determine dorsal and lateral identities, respectively. However, the molecular basis of how these two highly homologous genes orchestrate their diverse functions remains unclear. Here, we analyzed their expression levels, and investigated the transcriptional activities of SQUand KEW. We demonstrated that SQU possesses both activation and repression activities, while KEW acts only as an activator. They form homo- and heterodimers, and then collaboraUvely regulate their expression at the transcription level. Furthermore, we identified two types of post-transcriptional modifications, phosphor- ylation and ATP/GTP binding, both of which could affect their transcriptional activities. Mutations in ATP/ GTP binding motifs of SQU and KEW lead to failure of phosphorylation, and transgenic plants bearing the mutant proteins display defective DV asymmetric flower development, indicating that the two conjugate modifications are essential for their diverse functions. Altogether, SQU and KEW activities are precisely modulated at both transcription and post-transcription levels, which might link DV asymmetric flower development to different physiological status and/or signaling pathways.
基金This work was supported by the National Natural Science Foundation of China(No.51802310)All animal experiments were conducted according to protocols approved by the Institutional Animal Care and Use Committee in the Institute of Chemistry,Chinese Academy of Sciences.
文摘Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.
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.
基金The work was partially supported by the National Institutes of Health(NIH,grants No.P20GM113123 to J.H.,R01AI138203 and AI109317 to M.W.)the Science and Technology Department of Sichuan Province(grant No.2019YJ0050)to C.LThe funders of the study had no role in study design,data collection,data analysis,data interpretation,or writing of the paper.Influenza A virus(IAV,Puerto Rico/8/1934(H1N1))viral stocks were provided by the laboratory of Dr.NadeemKhan(University of North Dakota).Figure 1 was created by modifying illustrations provided by Servier Medical Art(SMART)licensed under a Creative Commons Attribution 3.0 Unported License(smart.servier.com)and Vecteezy.com.
文摘Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics,for example drug repurposing.To identify potentially repurposable drugs,we employed a systematic approach to mine candidates from U.S.FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients withmild and severe COVID-19(GEO:GSE145926,public data available and accessed on 22 April 2020).We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19.We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a,two chemical inhibitors of glycosylation(a post-translational modification)on the replication of the single-stranded ribonucleic acid(ssRNA)virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators(IFNs and ISGs).In conclusion,we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach,which may have the potential for treating these viral infections and their complications(sepsis).
基金provided by the British Heart Foundation,UK(Grant No.CH/15/1/31199)
文摘Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA （lncRNA）, a heteroge- neous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA （miRNA） pathways, lncRNA has been shown to act as both a source and an inhi- bitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying com- plexes by directing them to specific loci.
基金supported by the National Natural Science Foundation of China(91339113,81270202,81070095 to Xin HongBo)the National Basic Research Program of China(2013CB531103 to Xin HongBo)
文摘Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions,including impairment of the barrier functions,control of vascular tone,disturbance of proliferative and migratory capacity of endothelial cells,as well as control of leukocyte trafficking.Endothelial dysfunction is an early step in vascular inflammatory diseases such as atherosclerosis,diabetic vascular complications,sepsis-induced or severe virus infection-induced organ injuries.The expressions of inflammatory cytokines and vascular adhesion molecules induced by various stimuli,such as modified lipids,smoking,advanced glycation end products and bacteria toxin,significantly contribute to the development of endothelial dysfunction.The transcriptional regulation of inflammatory cytokines and vascular adhesion molecules has been well-studied.However,the regulation of those gene expressions at post-transcriptional level is emerging.RNA-binding proteins have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level in microRNA-dependent or independent manners.This review summarizes the latest insights into the roles of RNA-binding proteins in controlling vascular endothelial cell functions and their contribution to the pathogenesis of vascular inflammatory diseases.
基金Chongqing Science Fund for Distinguished Young Scholars(No.CSTB2022NSCQJQX0032)Chongqing University Innovation Research Group Project(No.CXQT21011)+2 种基金Chongqing Medical University Youth Innovation in Future Medicine(No.W0156)the National Natural Science Foundation of China(No.82200123)Natural Science Foundation of Chongqing,China,(No.CSTB2023NSCQ-MSX0280).
文摘Hematopoiesis represents a meticulously regulated and dynamic biological process.Genetic aberrations affecting blood cells,induced by various factors,frequently give rise to hematological tumors.These instances are often accompanied by a multitude of abnormal post-transcriptional regulatory events,including RNA alternative splicing,RNA localization,RNA degradation,and storage.Notably,post-transcriptional regulation plays a pivotal role in preserving hematopoietic homeostasis.The DEAD-Box RNA helicase genes emerge as crucial post-transcriptional regulatory factors,intricately involved in sustaining normal hematopoiesis through diverse mechanisms such as RNA alternative splicing,RNA modification,and ribosome assembly.This review consolidates the existing knowledge on the role of DEAD-box RNA helicases in regulating normal hematopoiesis and underscores the pathogenicity of mutant DEADBox RNA helicases in malignant hematopoiesis.Emphasis is placed on elucidating both the positive and negative contributions of DEAD-box RNA helicases within the hematopoietic system.
基金supported by the Innovation Program of Shanghai Municipal Education Commission(2023ZKZD05)the National Natural Science Foundation of China(32172043,31971918 and 32170356)+2 种基金the Shanghai Science and Technology Innovation Action Plan Project(22N11900200)the Innovation Program of Chinese Academy of Agricultural Sciencesthe grant from the National Key Research and Development Program of China(2021YFA1300401).
文摘RNA-binding proteins(RBPs)are components of the post-transcriptional regulatory system,but their regulatory effects on complex traits remain unknown.Using an integrated strategy involving map-based cloning,functional characterizations,and transcriptomic and population genomic analyses,we revealed that RBP-K(LOC_Os08g23120),RBP-A(LOC_Os11g41890),and RBP-J(LOC_Os10g33230)encode proteins that form an RBP-A-J-K complex that negatively regulates rice yield-related traits.Examinations of the RBP-A-J-K complex indicated RBP-K functions as a relatively non-specific RBP chaperone that enables RBP-A and RBP-J to function normally.Additionally,RBP-J most likely affects GA pathways,resulting in considerable increases in grain and panicle lengths,but decreases in grain width and thickness.In contrast,RBP-A negatively regulates the expression of genes most likely involved in auxin-regulated pathways controlling cell wall elongation and carbohydrate transport,with substantial effects on the rice grain filling process as well as grain length and weight.Evolutionarily,RBP-K is relatively ancient and highly conserved,whereas RBP-J and RBP-A are more diverse.Thus,the RBP-A-J-K complex may represent a typical functional model for many RBPs and protein complexes that function at transcriptional and post-transcriptional levels in plants and animals for increased functional consistency,efficiency,and versatility,as well as increased evolutionary potential.Our results clearly demonstrate the importance of RBP-mediated post-transcriptional regulation for the diversity of complex traits.Furthermore,rice grain yield and quality may be enhanced by introducing various complete or partial loss-of-function mutations to specific RBP genes using clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9 technology and by exploiting desirable natural tri-genic allelic combinations at the loci encoding the components of the RBP-A-J-K complex through marker-assisted selection.
文摘MicroRNAs(miRNAs)are a highly conserved class of small(18–24 nucleotides)non-coding RNAs that regulate a broad spectrum of biological processes.Aberrations or corruptions of miRNA functions may lead to deregulated cell proliferation,tumorigenesis,and ultimately,cancer.Increasing evidences suggested that a large fraction of miRNAs is regulated at the posttranscriptional stage,which impacts on the level and function of miRNAs during cell development and human diseases.Recently,several distinct mechanisms are emerging to regulate the biogenesis,stability and function of miRNAs at post-transcriptional level,such as specific binding to terminal loops of miRNA precursors(primiRNAs or pre-miRNAs)by RNA-binding proteins and 3’-terminal modifications by particular enzymes.Signaling cascades and post-translational modifications of the core components of RNA machinery also take part in the posttranscriptional regulation of miRNAs.
文摘猪繁殖与呼吸综合征(porcine reproductive and respiratory syndrome,PRRS)是由猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome virus,PRRSV)引起的以猪呼吸系统疾病和母猪繁殖障碍为主要特征的传染病,给全球养猪业造成了巨大的经济损失。然而,PRRS至今仍没有安全有效的疫苗和药物进行防治。全面深入理解PRRSV生命周期可以为PRRS防控提供新的思路。因此,本文在简述PRRSV生命周期的基础上,重点对病毒侵入、复制与转录、翻译及翻译后修饰、组装等过程的研究进展进行综述,以期为PRRSV致病机制及防控研究提供参考。
