In several stress responsive gene loci of monocot cereal crops,we have previously identified an unusual posttranscriptional processing mediated by paired presence of short direct repeated （SDR） sequences at 5＇ and ...In several stress responsive gene loci of monocot cereal crops,we have previously identified an unusual posttranscriptional processing mediated by paired presence of short direct repeated （SDR） sequences at 5＇ and 3＇ splicing junctions that are distinct from conventional （U2/U12-type） splicing boundaries.By using the known SDR-containing sequences as probes,24 plant candidate genes involved in diverse functional pathways from both monocots and dicots that potentially possess SDR-mediated posttranscriptional processing were predicted in the GenBank database.The SDRs-mediated posttranscriptional processing events including cis-and trans-actions were experimentally detected in majority of the predicted candidates.Extensive sequence analysis demonstrates several types of SDR-associated splicing peculiarities including partial exon deletion,exon fragment repetition,exon fragment scrambling and trans-splicing that result in either loss of partial exon or unusual exonic sequence rearrangements within or between RNA molecules.In addition,we show that the paired presence of SDR is necessary but not sufficient in SDR-mediated splicing in transient expression and stable transformation systems.We also show prokaryote is incapable of SDR-mediated premRNA splicing.展开更多
Extractable glycolipids of mycobacteria,such as lipooligosaccharides(LOSs),play crucial roles in responding to environmental stress and modulating the host immune response.Although the biosynthesis of LOS is likely re...Extractable glycolipids of mycobacteria,such as lipooligosaccharides(LOSs),play crucial roles in responding to environmental stress and modulating the host immune response.Although the biosynthesis of LOS is likely regulated at multiple levels to ensure proper composition of the cell wall,the key regulators remain unknown.In this study,we investigated B11,a conserved mycobacterial small RNA(sRNA),and found that it post-transcriptionally regulates LOS synthesis in Mycobacterium marinum.Through a combination of RNA-seq and mass spectrometry screening,we identified specific genes within the LOS synthesis locus that are directly regulated by B11.We confirmed in vivo sRNA-mRNA interactions using MS2-tagged RNA affinity purification,and found that B11 utilizes the cytosine-rich loop of its Rho-independent transcriptional terminator to interact with guanine tracks adjacent to the ribosome binding sites of its target genes,thereby impeding translation and promoting mRNA degradation.Moreover,deletion of B11 altered the colony morphology associated with LOS composition.These comprehensive functional studies of the mycobacterial sRNA B11 reveal sRNA-based regulation of LOS synthesis,providing new insights into the regulatory mechanisms controlling the biosynthesis of the complex mycobacterial cell wall.展开更多
The postharvest senescence phase of table grapes comprises a series of biological processes.MicroRNAs(miRNAs)regulate downstream genes at the post-transcriptional level;however,whether miRNAs are involved in postharve...The postharvest senescence phase of table grapes comprises a series of biological processes.MicroRNAs(miRNAs)regulate downstream genes at the post-transcriptional level;however,whether miRNAs are involved in postharvest grape senescence remains unclear.We used small RNA sequencing to identify postharvest-related miRNAs in‘Red Globe'(Vitis vinifera)grapes harvested after 0,30,and 60 d of storage at 4℃(RG0,RG30,RG60).In total,42 known and 219 novel miRNA candidates were obtained.During fruit senescence,the expression of PC-3p-3343_1921,mi R2950,miR395k,miR2111,miR159c,miR169q,PC-5p-1112_4500,and miR167b changed signifcantly(P<0.05).Degradation sequencing identifed 218 targets associated with cell wall organization,tricarboxylic acid(TCA)cycling,pathogen defense,carbon metabolism,hormone signaling,the anthocyanin metabolism pathway,and energy regulation,of which ARF6,GRF3,TCP2,CP1,MYBA2,and WRKY72 were closely related to fruit senescence.We also verified that VIT_00s2146g00010,VIT_02s0012g01750,and VIT_03s0038g00160 with unknown functions are cleaved by senescence-related PC-5p-1112_4500 via the dual luciferase assay,and the transient transformation of grape berries showed that they regulate berry senescence.These results deepen our understanding of the role of mi RNAs in regulating grape berry senescence and prolonging the shelf life of horticultural products.Based on these results,we propose a new theoretical strategy for delaying the postharvest senescence of horticultural products by regulating the expression of key miRNAs(e.g.,PC-5p-1112_4500),thereby extending their shelf life.展开更多
Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactiv...Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins （RBPs）, which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testis germ cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs our recent knowledge of the Musashi proteins in spermatogenesis. within the scope of male germ cell development, focusing on The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.展开更多
Ribonucleic acid （RNA） was previously thought to remain inside cells as an intermediate between genes and proteins during translation. However, it is now estimated that 98% of the mammalian genomic output is transcr...Ribonucleic acid （RNA） was previously thought to remain inside cells as an intermediate between genes and proteins during translation. However, it is now estimated that 98% of the mammalian genomic output is transcribed as noncoding RNAs, which are involved in diverse gene expression regulatory mechanisms and can be transferred from one cell to another through extracellular communication. For instance, microRNAs are 22-nucleotide-long noncoding RNAs that are generated by endonuclease cleavage of precursors inside the cells and are secreted as extracellular microRNAs to regulate target cell posttranscriptional gene expression via RNA interference. We and others have shown that different populations of microRNAs are expressed in distinct regions of the human epididymis and regulate the expression of target genes that are involved in the control of male fertility as indicated by knock-out mouse models. Importantly, some microRNAs, including the microRNA-888 （miR-888） cluster that is exclusively expressed in the reproductive system of human and nonhuman primates, are released in the sperm-surrounding fluid in the epididymis via extracellular vesicles, the so-called epididymosomes. In addition to interacting with the membrane of maturing spermatozoa, these extracellular vesicles containing microRNAs communicate with epithelial cells located downstream from their release site, suggesting a role in the luminal exocrine control of epididymal functions. Apart from their potential roles as mediators of intercellular communication within the epididymis, these extracellular microRNAs are potent molecular targets for the noninvasive diagnosis of male infertility.展开更多
Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for ...Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics.Highly conserved RNA-binding protein Pumilio-1(PUM1)regulates mouse growth and cell proliferation,propelling us to examine its role in cancer.We found human PUM1 is highly expressed in a diverse group of cancer,including prostate cancer;enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients.Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels.Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation,and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size.Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B(CDKN1B)protein expression through increased translation but did not impact its mRNA level,while overexpression of PUM1 reduced CDKN1B protein level.Our finding established a critical role of PUM1 mediated translational control,particularly the PUM1-CDKN1B axis,in prostate cancer cell growth and tumorigenesis.We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.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
Gastric cancer(GC)remains among the most common cancers worldwide with a high mortality-to-incidence ratio.Accumulated evidence suggests that long noncoding RNAs(lncRNAs)are involved in gastric carcinogenesis.These tr...Gastric cancer(GC)remains among the most common cancers worldwide with a high mortality-to-incidence ratio.Accumulated evidence suggests that long noncoding RNAs(lncRNAs)are involved in gastric carcinogenesis.These transcripts are longer than 200 nucleotides and modulate gene expression at multiple molecular levels,inducing or inhibiting biological processes and diseases.Metastasis-associated lung adenocarcinoma transcript 1(MALAT1)is one of the best-studied lncRNAs with comprehensive actions contributing to cancer progression.This lncRNA regulates gene expression at the transcriptional and posttranscriptional levels through interactions with microRNAs and proteins.In the present review,we discussed the molecular mechanism of MALAT1 and summarized the current knowledge of its expression in GC.Moreover,we highlighted the potential use of MALAT1 as a biomarker,including liquid biopsy.展开更多
MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that...MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that they have profoundly important functions in brain development and pathological processes. For example, miR-124 plays an important role in inducing and maintaining neuronal identity through targeting at least two anti-neural factors. MicroRNAs have also been implicated in brain disorders, including brain tumors and neurodegenerative diseases. This review aims to present an overview of the expression profiles and functions of microRNAs in the developing brains of vertebrates.展开更多
The specification of germ cells in zebrafish mostly relies on an inherited mechanism by which localized maternal determinants,called germ plasm,confer germline fate in the early embryo.Extensive studies have partially...The specification of germ cells in zebrafish mostly relies on an inherited mechanism by which localized maternal determinants,called germ plasm,confer germline fate in the early embryo.Extensive studies have partially allowed the identification of key regulators governing germ plasm formation and subsequent germ cell development.RNA-binding proteins,acting in concert with other germ plasm components,play essential roles in the organization of the germ plasm and the specification,migration,maintenance,and differentiation of primordial germ cells.The loss of their functions impairs germ cell formation and causes sterility or sexual conversion.Evidence is emerging that they instruct germline development through differential regulation of mRNA fates in somatic and germ cells.However,the challenge remains to decipher the complex interplay of maternal germ plasm components in germ plasm compartmentalization and germ cell specification.Because failure to control the developmental outcome of germ cells disrupts the formation of gametes,it is important to gain a complete picture of regulatory mechanisms operating in the germ cell lineage.This review sheds light on the contributions of RNA-binding proteins to germ cell development in zebrafish and highlights intriguing questions that remain open for future investigation.展开更多
BACKGROUND Locally advanced adenocarcinoma of the esophagus(EAC) and squamous cell carcinoma(ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane ...BACKGROUND Locally advanced adenocarcinoma of the esophagus(EAC) and squamous cell carcinoma(ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane glycoprotein podoplanin is overexpressed in squamous cell carcinomas, mi RNA-363 is associated to its regulation in head and neck cancer.AIM To predict therapy response and prognosis markers, and targets for novel therapies would individualize treatments leading to more favourable outcomes.METHODS Expression of podoplanin protein has been visualized by immunohistochemistry in surgical specimens of 195 esophageal cancer patients who underwent transthoracic esophagectomy: 90 ESCC and 105 EAC with clinical T2-3, Nx, M0.One hundred and six patients received neoadjuvant chemoradiation. RNA was extracted from paraffin-embedded tissue, and mi RNA-363 quantified by realtime Taq Man-real-time-PCR. D2-40 mab staining of > 5% was scored as high podoplanin expression(HPE). We related podoplanin and mi RNA-363 expression to histopathologic response after neoadjuvant treatment and clinicopathological characteristics, such as histological tumor type, survival rate or clinical tumor category.RESULTSWe confirmed expression of membrane-bound podoplanin in 90 ESCC patients.26% showed HPE of > 5%. In addition, absence in EAC patients(only 2% with HPE) was shown. Lower podoplanin expression has been detected in resectionspecimen of 58 ESCC patients after neoadjuvant(RTx/CTx) treatment, only 11% with HPE, compared to 50% HPE of 32 non-pretreated primary surgery patients,P = 0.0001. This difference of podoplanin expression was confirmed comparing pre-treatment biopsies with matching post-treatment surgical specimens, P <0.001. Podoplanin has been identified as a prognostic marker in 32 patients that underwent primary surgery without neoadjuvant treatment. Low(0-5%)podoplanin expression was associated with better prognosis compared to patients with HPE, P = 0.013. Podoplanin expression has been associated with post-transcriptional regulation by mi RNA-363. At a cut-off value of miR-363 < 7,lower mi R-363 expression correlated with HPE in surgical tissue specimens of primary surgery patients, P = 0.013. Therefore, ESCC patients with mi RNA-363 expression < 7 had a worse prognosis than patients expressing mi RNA-363 ≥ 7, P= 0.049.CONCLUSION Analysis of the molecular process that leads to decrease in podoplanin expression during neoadjuvant treatment and its regulation may provide novel markers and targets to improve targeted therapy of ESCC.展开更多
Objective: To investigate the post-transcriptional regulation of p21WAF1/CIP1 by p53. Methods: The MDA-MB-468 cells have endogenous mutant p53 and the MCF7 cells lines have wtp53. Recombinant p53 expression and p21WAF...Objective: To investigate the post-transcriptional regulation of p21WAF1/CIP1 by p53. Methods: The MDA-MB-468 cells have endogenous mutant p53 and the MCF7 cells lines have wtp53. Recombinant p53 expression and p21WAF1/CIP1 induction were detected by Western blot analysis. Northern blot analysis was carried out to examine whether changes in p21WAF1/CIP1 protein levels in MCF7 cells treated with AdCMVp53 are reflected at the mRNA level. Flow cytometric analysis of MCF7 cells following overexpression of recombination. Results: The ratio of p53: p21WAF1/CIP1 was below 1 at the early stages of AdCMVp53 infection, but increased to 1.6 by day 3 and to 9.7 by day 5 post-infection. As expected, p21WAF1/CIP1 expression was not detectable in MDA-MB-468 cells despite the presence of high levels of mutant p53 protein. The G1/S ratios in untreated controls and AdCMVβgal infected MCF7 cells were 1.10 and 1.35, respectively. By Northern blot analyzing the p21WAF1/CIP1: GAPDH ratios at different time points against the ratio at time point 0, a maximum 3-fold induction of p21WAF1/CIP1 mRNA expression relative to untreated control was observed on day 1 post-infection. The flow cytometric analysis indicated that MCF7 cells infected with AdCMVp53 undergo G1 arrest at both time points studied, with G1/S ratios ranging from 5.54 at day 1 to 5.65 at day 7. The G1/S ratios in untreated controls and AdCMVβgal infected MCF7 cells were 1.10 and 1.35, respectively. Conclusion: This study demonstrated that p53 could regulate p21WAF1/CIP1 gene expression at both the transcriptional and post-transcriptional levels in MCF7 cells. The latter mechanism may be involved in or be responsible for, the induction of cell cycle arrest by transcription-defective mutants of p53.展开更多
Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening pa...Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs. Posttranscriptional mechanisms such as mRNA degradation and translational repression are responsible for the final synthesis of the required protein products. In this context, RNA-binding proteins(RBPs) in trypanosomes have a relevant role as modulators of mRNA abundance and translational repression by associating to the 3' untranslated regions in mRNA. Many different RBPs have been proposed to modulate cohorts of mRNAs in trypanosomes. However, the current understanding of their functions lacks a dynamic view on the different steps at which these RBPs are regulated. Here, we discuss different evidences to propose regulatory events for different RBPs in these parasites. These events vary from regulated developmental expression, to biogenesis of cytoplasmic ribonucleoprotein complexes in the nucleus, and condensation of RBPs and mRNA into large cytoplasmic granules. Finally, we discuss how newly identified posttranslational modifications of RBPs and mRNA metabolism-related proteins could have an enormous impact on the modulation of m RNA abundance. To understand these modifications is especially relevant in these parasites due to the fact that the enzymes involved could be interesting targets for drug therapy.展开更多
Till now the transcription factor Xvent-2 has been studied in Xenopus embryos only by the mRNA testing. We use immunochemical methods for testing of the Xvent-2 protein and gradient-centrifugation methods for estimati...Till now the transcription factor Xvent-2 has been studied in Xenopus embryos only by the mRNA testing. We use immunochemical methods for testing of the Xvent-2 protein and gradient-centrifugation methods for estimation of activity of its mRNA. Our results show that the Xvent-2 protein is present in eggs and early embryos. The Xvent-2 mRNA is absent at any of these developmental stages. The majority of mRNA synthesized on the zygotic genome was stored in informosomes, while only its small part could be revealed in polysomes. The spatial patterning of the Xvent-2 protein at different developmental stages did not entirely agree with that of its mRNA. These data indicate that the Xvent-2 protein functioning in Xenopu embryos is regulated not only at the transcription, but at translation and posttranslation as well. We propose that the activation of translation on the masked Xvent-2 mRNA may lead to blood differentiation and cell migration.展开更多
Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose postt...Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.展开更多
In the present study, we examine the effects of the treatment with 1,25-dihydroxyvitamin D3 [150 IU/Kg (3.75 μg/Kg) once a day, for 15 days] to non-diabetic and streptozotocin-induced diabetic rats. The results indic...In the present study, we examine the effects of the treatment with 1,25-dihydroxyvitamin D3 [150 IU/Kg (3.75 μg/Kg) once a day, for 15 days] to non-diabetic and streptozotocin-induced diabetic rats. The results indicate that treatment with 1,25-dihydroxyvitamin D3 had minor effects in non-diabetic rats. The same treatment in streptozotocin-induced diabetic rats, although it did not correct the hyperglycemia and hypoinsulinemia induced by the diabetes, caused other actions that could mean beneficial effects on the amelioration of diabetes e.g., it avoided body weight loss, increased calcium and phosphorus plasma levels, and corrected the over-expression of the insulin receptor mRNA species of 9.5 and 7.5 Kb present in the hind limb muscle and heart of these animals. These genomic 1,25-dihydroxyvitamin D3 effects could involve transcriptional mechanisms of repression mediated by vitamin D response elements in the rat insulin receptor gene promoter. Using computer analysis of this promoter, we propose the -249/-235 bp VDRE (5’GGGTGACCCGGGGTT3’) with a pyrimidine (T) in the (+7) position of the3’half-site as the best candidate for negative control by 1,25-dihydroxy-vitamin D3. In addition, posttranscriptional mechanisms of regulation could also be implicated. Thus, computer inspection of the5’untranslated region of the rat insulin receptor pre-mRNA indicated the presence of a virtual internal ribosome entry segment whereas the computer inspection of the3’untranslated region localized various destabilizing sequences, including various AU-rich elements. We propose that through these virtual cis-regulatory sequences, 1,25-dihydroxyvitamin D3 could control the translation and stability of insulin receptor mRNA species in the hind limb muscle and heart of diabetic rats.展开更多
Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of bi...Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates.Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss.Nevertheless,there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss.In this review,we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss,specifically focusing on its effects on mechanoelectrical transduction in hair bundles,transcriptional regulation,post-transcriptional modifications,the actin cytoskeleton,ion homeostasis within the inner ear,and energy and redox homeostasis.Furthermore,we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.展开更多
In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammat...In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammatory response in coordination with transcriptional regulation.However,among these posttranscriptional mechanisms,very little is known regarding the role of alternative polyadenylation(APA),a process that generates transcripts with different 3'ends,in modulating gene expression during inflammation.In a paper published on this topic,Chen and coworkers provided evidence indicating that alternative polyadenylation promotes macrophage inflammatory functions by modulating the expression of genes involved in the autophagy pathway[1].展开更多
On October 7, the Nobel Assembly at Sweden's Karolinska Institute announced the awarding of the 2024 Nobel Prize in Physiology or Medicine to American scientists Victor Ambros and Gary Ruvkun for their discovery o...On October 7, the Nobel Assembly at Sweden's Karolinska Institute announced the awarding of the 2024 Nobel Prize in Physiology or Medicine to American scientists Victor Ambros and Gary Ruvkun for their discovery of microRNAs and their role in posttranscriptional gene regulation.展开更多
N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development...N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.展开更多
基金supported by the National Key Basic Research Program (973 program) (No. 2006CB100205)the National Science Fund for Distinguished Young Scholars (No. 30825030)+2 种基金the National Natural Science Foundation of China (No. 30770466, 90717110, 30970260 and 30971752)the Earmarked Fund for Modern Agro-industry Technology Research System (No. nycytx-01)the National High Technology Research and Development Program of China (863 Program) (No. 2007AA10Z100)
文摘In several stress responsive gene loci of monocot cereal crops,we have previously identified an unusual posttranscriptional processing mediated by paired presence of short direct repeated （SDR） sequences at 5＇ and 3＇ splicing junctions that are distinct from conventional （U2/U12-type） splicing boundaries.By using the known SDR-containing sequences as probes,24 plant candidate genes involved in diverse functional pathways from both monocots and dicots that potentially possess SDR-mediated posttranscriptional processing were predicted in the GenBank database.The SDRs-mediated posttranscriptional processing events including cis-and trans-actions were experimentally detected in majority of the predicted candidates.Extensive sequence analysis demonstrates several types of SDR-associated splicing peculiarities including partial exon deletion,exon fragment repetition,exon fragment scrambling and trans-splicing that result in either loss of partial exon or unusual exonic sequence rearrangements within or between RNA molecules.In addition,we show that the paired presence of SDR is necessary but not sufficient in SDR-mediated splicing in transient expression and stable transformation systems.We also show prokaryote is incapable of SDR-mediated premRNA splicing.
基金supported by the Natural Science Foundation of China(81991532 and 32170179 to C.W.and 82272376 to Q.G.)National Key R&D Program of China(2022YFE0111800 to C.W.)the Shanghai Municipal Science and Technology Major Project(ZD2021CY001).
文摘Extractable glycolipids of mycobacteria,such as lipooligosaccharides(LOSs),play crucial roles in responding to environmental stress and modulating the host immune response.Although the biosynthesis of LOS is likely regulated at multiple levels to ensure proper composition of the cell wall,the key regulators remain unknown.In this study,we investigated B11,a conserved mycobacterial small RNA(sRNA),and found that it post-transcriptionally regulates LOS synthesis in Mycobacterium marinum.Through a combination of RNA-seq and mass spectrometry screening,we identified specific genes within the LOS synthesis locus that are directly regulated by B11.We confirmed in vivo sRNA-mRNA interactions using MS2-tagged RNA affinity purification,and found that B11 utilizes the cytosine-rich loop of its Rho-independent transcriptional terminator to interact with guanine tracks adjacent to the ribosome binding sites of its target genes,thereby impeding translation and promoting mRNA degradation.Moreover,deletion of B11 altered the colony morphology associated with LOS composition.These comprehensive functional studies of the mycobacterial sRNA B11 reveal sRNA-based regulation of LOS synthesis,providing new insights into the regulatory mechanisms controlling the biosynthesis of the complex mycobacterial cell wall.
基金supported by the Natural Science Foundation of Ningxia,China(2024AAC02039)the Scientific and Technological Innovation Leadership Talent Program of Ningxia,China(2022GKLRLX07)+1 种基金the National Natural Science Foundation of China(32260727 and 32371924)China Agriculture Research System(CARS-29-zp-6)。
文摘The postharvest senescence phase of table grapes comprises a series of biological processes.MicroRNAs(miRNAs)regulate downstream genes at the post-transcriptional level;however,whether miRNAs are involved in postharvest grape senescence remains unclear.We used small RNA sequencing to identify postharvest-related miRNAs in‘Red Globe'(Vitis vinifera)grapes harvested after 0,30,and 60 d of storage at 4℃(RG0,RG30,RG60).In total,42 known and 219 novel miRNA candidates were obtained.During fruit senescence,the expression of PC-3p-3343_1921,mi R2950,miR395k,miR2111,miR159c,miR169q,PC-5p-1112_4500,and miR167b changed signifcantly(P<0.05).Degradation sequencing identifed 218 targets associated with cell wall organization,tricarboxylic acid(TCA)cycling,pathogen defense,carbon metabolism,hormone signaling,the anthocyanin metabolism pathway,and energy regulation,of which ARF6,GRF3,TCP2,CP1,MYBA2,and WRKY72 were closely related to fruit senescence.We also verified that VIT_00s2146g00010,VIT_02s0012g01750,and VIT_03s0038g00160 with unknown functions are cleaved by senescence-related PC-5p-1112_4500 via the dual luciferase assay,and the transient transformation of grape berries showed that they regulate berry senescence.These results deepen our understanding of the role of mi RNAs in regulating grape berry senescence and prolonging the shelf life of horticultural products.Based on these results,we propose a new theoretical strategy for delaying the postharvest senescence of horticultural products by regulating the expression of key miRNAs(e.g.,PC-5p-1112_4500),thereby extending their shelf life.
文摘Controlled gene regulation during gamete development is vital for maintaining reproductive potential. During the complex process of mammalian spermatogenesis, male germ cells experience extended periods of the inactive transcription despite heavy translational requirements for continued growth and differentiation. Hence, spermatogenesis is highly reliant on mechanisms of posttranscriptional regulation of gene expression, facilitated by RNA binding proteins （RBPs）, which remain abundantly expressed throughout this process. One such group of proteins is the Musashi family, previously identified as critical regulators of testis germ cell development and meiosis in Drosophila, and also shown to be vital to sperm development and reproductive potential in the mouse. This review describes the role and function of RBPs our recent knowledge of the Musashi proteins in spermatogenesis. within the scope of male germ cell development, focusing on The functional mechanisms utilized by RBPs within the cell are outlined in depth, and the significance of sub-cellular localization and stage-specific expression in relation to the mode and impact of posttranscriptional regulation is also highlighted. We emphasize the historical role of the Musashi family of RBPs in stem cell function and cell fate determination, as originally characterized in Drosophila and Xenopus, and conclude with our current understanding of the differential roles and functions of the mammalian Musashi proteins, Musashi-1 and Musashi-2, with a primary focus on our findings in spermatogenesis. This review highlights both the essential contribution of RBPs to posttranscriptional regulation and the importance of the Musashi family as master regulators of male gamete development.
文摘Ribonucleic acid （RNA） was previously thought to remain inside cells as an intermediate between genes and proteins during translation. However, it is now estimated that 98% of the mammalian genomic output is transcribed as noncoding RNAs, which are involved in diverse gene expression regulatory mechanisms and can be transferred from one cell to another through extracellular communication. For instance, microRNAs are 22-nucleotide-long noncoding RNAs that are generated by endonuclease cleavage of precursors inside the cells and are secreted as extracellular microRNAs to regulate target cell posttranscriptional gene expression via RNA interference. We and others have shown that different populations of microRNAs are expressed in distinct regions of the human epididymis and regulate the expression of target genes that are involved in the control of male fertility as indicated by knock-out mouse models. Importantly, some microRNAs, including the microRNA-888 （miR-888） cluster that is exclusively expressed in the reproductive system of human and nonhuman primates, are released in the sperm-surrounding fluid in the epididymis via extracellular vesicles, the so-called epididymosomes. In addition to interacting with the membrane of maturing spermatozoa, these extracellular vesicles containing microRNAs communicate with epithelial cells located downstream from their release site, suggesting a role in the luminal exocrine control of epididymal functions. Apart from their potential roles as mediators of intercellular communication within the epididymis, these extracellular microRNAs are potent molecular targets for the noninvasive diagnosis of male infertility.
基金supported by the National Natural Science Foundation of China(Grant No.31771652 and No.81270737).
文摘Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics.Highly conserved RNA-binding protein Pumilio-1(PUM1)regulates mouse growth and cell proliferation,propelling us to examine its role in cancer.We found human PUM1 is highly expressed in a diverse group of cancer,including prostate cancer;enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients.Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels.Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation,and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size.Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B(CDKN1B)protein expression through increased translation but did not impact its mRNA level,while overexpression of PUM1 reduced CDKN1B protein level.Our finding established a critical role of PUM1 mediated translational control,particularly the PUM1-CDKN1B axis,in prostate cancer cell growth and tumorigenesis.We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.
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Gastric cancer(GC)remains among the most common cancers worldwide with a high mortality-to-incidence ratio.Accumulated evidence suggests that long noncoding RNAs(lncRNAs)are involved in gastric carcinogenesis.These transcripts are longer than 200 nucleotides and modulate gene expression at multiple molecular levels,inducing or inhibiting biological processes and diseases.Metastasis-associated lung adenocarcinoma transcript 1(MALAT1)is one of the best-studied lncRNAs with comprehensive actions contributing to cancer progression.This lncRNA regulates gene expression at the transcriptional and posttranscriptional levels through interactions with microRNAs and proteins.In the present review,we discussed the molecular mechanism of MALAT1 and summarized the current knowledge of its expression in GC.Moreover,we highlighted the potential use of MALAT1 as a biomarker,including liquid biopsy.
基金the Key Basic Research Developing Project of China (973 Project), No.2007CB947001the State High Technology Development and Research Project of China (863 Project), No.2008AA02Z115+1 种基金the Key Program of National Natural Science Foundation of China, No.30430240Shanghai Metropolitan Fund for Research and Development, No. 04DZ14005,04JC14096
文摘MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that they have profoundly important functions in brain development and pathological processes. For example, miR-124 plays an important role in inducing and maintaining neuronal identity through targeting at least two anti-neural factors. MicroRNAs have also been implicated in brain disorders, including brain tumors and neurodegenerative diseases. This review aims to present an overview of the expression profiles and functions of microRNAs in the developing brains of vertebrates.
文摘The specification of germ cells in zebrafish mostly relies on an inherited mechanism by which localized maternal determinants,called germ plasm,confer germline fate in the early embryo.Extensive studies have partially allowed the identification of key regulators governing germ plasm formation and subsequent germ cell development.RNA-binding proteins,acting in concert with other germ plasm components,play essential roles in the organization of the germ plasm and the specification,migration,maintenance,and differentiation of primordial germ cells.The loss of their functions impairs germ cell formation and causes sterility or sexual conversion.Evidence is emerging that they instruct germline development through differential regulation of mRNA fates in somatic and germ cells.However,the challenge remains to decipher the complex interplay of maternal germ plasm components in germ plasm compartmentalization and germ cell specification.Because failure to control the developmental outcome of germ cells disrupts the formation of gametes,it is important to gain a complete picture of regulatory mechanisms operating in the germ cell lineage.This review sheds light on the contributions of RNA-binding proteins to germ cell development in zebrafish and highlights intriguing questions that remain open for future investigation.
文摘BACKGROUND Locally advanced adenocarcinoma of the esophagus(EAC) and squamous cell carcinoma(ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane glycoprotein podoplanin is overexpressed in squamous cell carcinomas, mi RNA-363 is associated to its regulation in head and neck cancer.AIM To predict therapy response and prognosis markers, and targets for novel therapies would individualize treatments leading to more favourable outcomes.METHODS Expression of podoplanin protein has been visualized by immunohistochemistry in surgical specimens of 195 esophageal cancer patients who underwent transthoracic esophagectomy: 90 ESCC and 105 EAC with clinical T2-3, Nx, M0.One hundred and six patients received neoadjuvant chemoradiation. RNA was extracted from paraffin-embedded tissue, and mi RNA-363 quantified by realtime Taq Man-real-time-PCR. D2-40 mab staining of > 5% was scored as high podoplanin expression(HPE). We related podoplanin and mi RNA-363 expression to histopathologic response after neoadjuvant treatment and clinicopathological characteristics, such as histological tumor type, survival rate or clinical tumor category.RESULTSWe confirmed expression of membrane-bound podoplanin in 90 ESCC patients.26% showed HPE of > 5%. In addition, absence in EAC patients(only 2% with HPE) was shown. Lower podoplanin expression has been detected in resectionspecimen of 58 ESCC patients after neoadjuvant(RTx/CTx) treatment, only 11% with HPE, compared to 50% HPE of 32 non-pretreated primary surgery patients,P = 0.0001. This difference of podoplanin expression was confirmed comparing pre-treatment biopsies with matching post-treatment surgical specimens, P <0.001. Podoplanin has been identified as a prognostic marker in 32 patients that underwent primary surgery without neoadjuvant treatment. Low(0-5%)podoplanin expression was associated with better prognosis compared to patients with HPE, P = 0.013. Podoplanin expression has been associated with post-transcriptional regulation by mi RNA-363. At a cut-off value of miR-363 < 7,lower mi R-363 expression correlated with HPE in surgical tissue specimens of primary surgery patients, P = 0.013. Therefore, ESCC patients with mi RNA-363 expression < 7 had a worse prognosis than patients expressing mi RNA-363 ≥ 7, P= 0.049.CONCLUSION Analysis of the molecular process that leads to decrease in podoplanin expression during neoadjuvant treatment and its regulation may provide novel markers and targets to improve targeted therapy of ESCC.
文摘Objective: To investigate the post-transcriptional regulation of p21WAF1/CIP1 by p53. Methods: The MDA-MB-468 cells have endogenous mutant p53 and the MCF7 cells lines have wtp53. Recombinant p53 expression and p21WAF1/CIP1 induction were detected by Western blot analysis. Northern blot analysis was carried out to examine whether changes in p21WAF1/CIP1 protein levels in MCF7 cells treated with AdCMVp53 are reflected at the mRNA level. Flow cytometric analysis of MCF7 cells following overexpression of recombination. Results: The ratio of p53: p21WAF1/CIP1 was below 1 at the early stages of AdCMVp53 infection, but increased to 1.6 by day 3 and to 9.7 by day 5 post-infection. As expected, p21WAF1/CIP1 expression was not detectable in MDA-MB-468 cells despite the presence of high levels of mutant p53 protein. The G1/S ratios in untreated controls and AdCMVβgal infected MCF7 cells were 1.10 and 1.35, respectively. By Northern blot analyzing the p21WAF1/CIP1: GAPDH ratios at different time points against the ratio at time point 0, a maximum 3-fold induction of p21WAF1/CIP1 mRNA expression relative to untreated control was observed on day 1 post-infection. The flow cytometric analysis indicated that MCF7 cells infected with AdCMVp53 undergo G1 arrest at both time points studied, with G1/S ratios ranging from 5.54 at day 1 to 5.65 at day 7. The G1/S ratios in untreated controls and AdCMVβgal infected MCF7 cells were 1.10 and 1.35, respectively. Conclusion: This study demonstrated that p53 could regulate p21WAF1/CIP1 gene expression at both the transcriptional and post-transcriptional levels in MCF7 cells. The latter mechanism may be involved in or be responsible for, the induction of cell cycle arrest by transcription-defective mutants of p53.
基金Supported by The Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)to Alejandro Cassola
文摘Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs. Posttranscriptional mechanisms such as mRNA degradation and translational repression are responsible for the final synthesis of the required protein products. In this context, RNA-binding proteins(RBPs) in trypanosomes have a relevant role as modulators of mRNA abundance and translational repression by associating to the 3' untranslated regions in mRNA. Many different RBPs have been proposed to modulate cohorts of mRNAs in trypanosomes. However, the current understanding of their functions lacks a dynamic view on the different steps at which these RBPs are regulated. Here, we discuss different evidences to propose regulatory events for different RBPs in these parasites. These events vary from regulated developmental expression, to biogenesis of cytoplasmic ribonucleoprotein complexes in the nucleus, and condensation of RBPs and mRNA into large cytoplasmic granules. Finally, we discuss how newly identified posttranslational modifications of RBPs and mRNA metabolism-related proteins could have an enormous impact on the modulation of m RNA abundance. To understand these modifications is especially relevant in these parasites due to the fact that the enzymes involved could be interesting targets for drug therapy.
文摘Till now the transcription factor Xvent-2 has been studied in Xenopus embryos only by the mRNA testing. We use immunochemical methods for testing of the Xvent-2 protein and gradient-centrifugation methods for estimation of activity of its mRNA. Our results show that the Xvent-2 protein is present in eggs and early embryos. The Xvent-2 mRNA is absent at any of these developmental stages. The majority of mRNA synthesized on the zygotic genome was stored in informosomes, while only its small part could be revealed in polysomes. The spatial patterning of the Xvent-2 protein at different developmental stages did not entirely agree with that of its mRNA. These data indicate that the Xvent-2 protein functioning in Xenopu embryos is regulated not only at the transcription, but at translation and posttranslation as well. We propose that the activation of translation on the masked Xvent-2 mRNA may lead to blood differentiation and cell migration.
文摘Posttranscriptional regulations of different types of RNA,including rRNA,tRNA,mRNA and ncRNA are widely involved in normal physiology and diseases.m RNA,as the intermediary product between gene and protein,whose posttranscriptional regulations such as alternative splicing,alternative polyadenylation and modifications impact its coded protein expression and functions.However,the functional significance and therapeutic potential of RNA posttranscriptional regulations are not well studied due to the lack of suitable RNA engineering platforms.The discovery of a novel CRISPR-Cas system termed CRISPR-Cas13 in 2015 that specifically targets RNA templates brought a new role to CRISPR to target and edit RNA with high specificity,which opened a new era of RNA manipulations to some degree.This review will summarize the emerging applications of the catalytically inactive CRISPR-Cas13 system(CRISPR-dCas13)in mRNA engineering and highlight the prospection of the CRISPR-dCas13 system for other RNA modification regulations and its therapeutic potential.
基金This work was supported by research Funds from the Ministerio de Ciencia e Innovación(SAF2009-12671).
文摘In the present study, we examine the effects of the treatment with 1,25-dihydroxyvitamin D3 [150 IU/Kg (3.75 μg/Kg) once a day, for 15 days] to non-diabetic and streptozotocin-induced diabetic rats. The results indicate that treatment with 1,25-dihydroxyvitamin D3 had minor effects in non-diabetic rats. The same treatment in streptozotocin-induced diabetic rats, although it did not correct the hyperglycemia and hypoinsulinemia induced by the diabetes, caused other actions that could mean beneficial effects on the amelioration of diabetes e.g., it avoided body weight loss, increased calcium and phosphorus plasma levels, and corrected the over-expression of the insulin receptor mRNA species of 9.5 and 7.5 Kb present in the hind limb muscle and heart of these animals. These genomic 1,25-dihydroxyvitamin D3 effects could involve transcriptional mechanisms of repression mediated by vitamin D response elements in the rat insulin receptor gene promoter. Using computer analysis of this promoter, we propose the -249/-235 bp VDRE (5’GGGTGACCCGGGGTT3’) with a pyrimidine (T) in the (+7) position of the3’half-site as the best candidate for negative control by 1,25-dihydroxy-vitamin D3. In addition, posttranscriptional mechanisms of regulation could also be implicated. Thus, computer inspection of the5’untranslated region of the rat insulin receptor pre-mRNA indicated the presence of a virtual internal ribosome entry segment whereas the computer inspection of the3’untranslated region localized various destabilizing sequences, including various AU-rich elements. We propose that through these virtual cis-regulatory sequences, 1,25-dihydroxyvitamin D3 could control the translation and stability of insulin receptor mRNA species in the hind limb muscle and heart of diabetic rats.
基金supported by the National Natural Science Foundation of China(82430035)the Foundation for Innovative Research Groups of Hubei Province(2023AFA038)+1 种基金the National Key Research and Development Program of China(2021YFF0702303,2024YFC2511101,and 2023YFE0203200)the Fundamental Research Funds for the Central Universities(2024BRA019).
文摘Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates.Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss.Nevertheless,there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss.In this review,we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss,specifically focusing on its effects on mechanoelectrical transduction in hair bundles,transcriptional regulation,post-transcriptional modifications,the actin cytoskeleton,ion homeostasis within the inner ear,and energy and redox homeostasis.Furthermore,we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.
文摘In recent years,posttranscriptional cellular processes such as alternative splicing,messenger RNA(mRNA)decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammatory response in coordination with transcriptional regulation.However,among these posttranscriptional mechanisms,very little is known regarding the role of alternative polyadenylation(APA),a process that generates transcripts with different 3'ends,in modulating gene expression during inflammation.In a paper published on this topic,Chen and coworkers provided evidence indicating that alternative polyadenylation promotes macrophage inflammatory functions by modulating the expression of genes involved in the autophagy pathway[1].
文摘On October 7, the Nobel Assembly at Sweden's Karolinska Institute announced the awarding of the 2024 Nobel Prize in Physiology or Medicine to American scientists Victor Ambros and Gary Ruvkun for their discovery of microRNAs and their role in posttranscriptional gene regulation.
文摘N^6-methyladenosine(m^6A)emerges as an important modification in eukaryotic mRNAs.m^6A has first been reported in 1974,and its functional significance in mammalian gene regulation and importance for proper development have been well established.An arsenal of writer,eraser,and reader proteins accomplish deposition,removal,and interpretation of the m^6A mark,resulting in dynamic function.This led to the concept of an epitranscriptome,the compendium of RNA species with chemical modification ofthe nucleobases in the cell,in analogy to the epigenome.While m^6A has long been known to also exist in plant mRNAs,proteins involved in m^6A metabolism have only recently been detected by mutant analysis,homology search,and mRNA interactome capture in the reference plant Arabidopsis thaliana.Dysregulation ofthe m^6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development.Furthermore,m^6A modification affects viral infection.Here,we discuss recent progress in identifying m^6A sites transcriptome-wide,in identifying the molecular players involved in writing,removing,and reading the mark,and in assigning functions to this RNA modification in 4.thaliana.We highlight similarities and differences to m^6A modification in mammals and provide an outlook on important questions that remain to be addressed.
