RESUMO
Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.
Assuntos
Neoplasias Meníngeas , Meningioma , Transcriptoma , Meningioma/genética , Meningioma/patologia , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Algoritmos , Perfilação da Expressão Gênica/métodosRESUMO
Clinical and experimental studies have established that immune cells such as alternatively activated (M2) macrophages and Th17 cells play a role in the progression of chronic kidney disease, but the endogenous pathways that limit these processes are not well understood. The cytokine IL-27 has been shown to limit immune-mediated pathology in other systems by effects on these cell types, but this has not been thoroughly investigated in the kidney. Unilateral ureteral obstruction was performed on wild-type and IL-27Rα-/- mice. After 2 wk, kidneys were extracted, and the degree of injury was measured by hydroxyproline assay and quantification of neutrophil gelatinase-associated lipocalin mRNA. Immune cell infiltrate was evaluated by immunohistochemistry and flow cytometry. An anti-IL-17A mAb was subsequently administered to IL-27Rα-/- mice every 2 d from day of surgery with evaluation as described after 2 wk. After unilateral ureteral obstruction, IL-27 deficiency resulted in increased tissue injury and collagen deposition associated with higher levels of chemokine mRNA and increased numbers of M2 macrophages. Loss of the IL-27Rα led to increased infiltration of activated CD4+ T cells that coproduced IL-17A and TNF-α, and blockade of IL-17A partially ameliorated kidney injury. Patients with chronic kidney disease had elevated serum levels of IL-27 and IL-17A, whereas expression of transcripts for the IL-27RA and the IL-17RA in the tubular epithelial cells of patients with renal fibrosis correlated with disease severity. These data suggest that endogenous IL-27 acts at several points in the inflammatory cascade to limit the magnitude of immune-mediated damage to the kidney.
Assuntos
Rim/patologia , Macrófagos/imunologia , Nefrite Intersticial/imunologia , Receptores de Interleucina/metabolismo , Células Th17/imunologia , Animais , Movimento Celular , Células Cultivadas , Progressão da Doença , Fibrose , Humanos , Interleucina-17/sangue , Interleucina-27/sangue , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina/genética , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismoRESUMO
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Assuntos
Doenças Cardiovasculares/sangue , Marcadores Genéticos , Gota/sangue , Doenças Metabólicas/sangue , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/epidemiologia , Gota/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Proteínas de Neoplasias/genética , Especificidade de ÓrgãosRESUMO
Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfamflox/flox). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.
Assuntos
DNA Mitocondrial/metabolismo , Túbulos Renais/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose , Humanos , Inflamação/patologia , Túbulos Renais/patologia , Masculino , Camundongos , Proteínas Mitocondriais/metabolismo , Células RAW 264.7 , Fatores de Transcrição/metabolismoRESUMO
In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1-based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.
Assuntos
Metilação de DNA/genética , Nefropatias Diabéticas , Epigenoma/genética , Animais , Diabetes Mellitus Experimental , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Humanos , Rim/metabolismo , Camundongos , Transcriptoma/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Sequenciamento Completo do GenomaRESUMO
Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.
Assuntos
Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Adulto , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/sangue , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteômica , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/genética , Fatores de RiscoRESUMO
Chronic kidney disease (CKD), a condition in which the kidneys are unable to clear waste products, affects 700 million people globally. Genome-wide association studies (GWASs) have identified sequence variants for CKD; however, the biological basis of these GWAS results remains poorly understood. To address this issue, we created an expression quantitative trait loci (eQTL) atlas for the glomerular and tubular compartments of the human kidney. Through integrating the CKD GWAS with eQTL, single-cell RNA sequencing and regulatory region maps, we identified novel genes for CKD. Putative causal genes were enriched for proximal tubule expression and endolysosomal function, where DAB2, an adaptor protein in the TGF-ß pathway, formed a central node. Functional experiments confirmed that reducing Dab2 expression in renal tubules protected mice from CKD. In conclusion, compartment-specific eQTL analysis is an important avenue for the identification of novel genes and cellular pathways involved in CKD development and thus potential new opportunities for its treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Insuficiência Renal Crônica/genética , Proteínas Supressoras de Tumor/genética , Animais , Proteínas Reguladoras de Apoptose , Compartimento Celular/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Camundongos , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)-induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule-specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteína Jagged-1/metabolismo , Rim/metabolismo , Rim/patologia , Proteínas Mitocondriais/metabolismo , Receptor Notch2/metabolismo , Fatores de Transcrição/metabolismo , Animais , Desdiferenciação Celular , Proliferação de Células , Células Epiteliais/metabolismo , Fibrose , Ontologia Genética , Genótipo , Humanos , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de SinaisRESUMO
Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1ß) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1ß. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1ß loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1ß-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.
Assuntos
Cistos/prevenção & controle , Metabolismo Energético , Epigenômica , Regulação da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/genética , Receptores de Estrogênio/genética , Insuficiência Renal Crônica/prevenção & controle , Animais , Cistos/metabolismo , Cistos/patologia , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 1-beta Nuclear de Hepatócito/fisiologia , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/fisiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologiaRESUMO
Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.
Assuntos
Metilação de DNA/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Idoso , Sítios de Ligação/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Ilhas de CpG , Progressão da Doença , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Epigênese Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Proibitinas , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
KEY MESSAGE: Casbene is a precursor to phorbol esters and down-regulating casbene synthase effectively reduces phorbol ester biosynthesis. Seed-specific reduction of phorbol ester (PE) helps develop Jatropha seed cake for animal nutrition. Phorbol esters (PEs) are diterpenoids present in some Euphorbiaceae family members like Jatropha curcas L. (Jatropha), a tropical shrub yielding high-quality oil suitable as feedstock for biodiesel and bio jet fuel. Jatropha seed contains up to 40 % of oil and can produce oil together with cake containing high-quality proteins. However, skin-irritating and cancer-promoting PEs make Jatropha cake meal unsuitable for animal nutrition and also raise some safety and environmental concerns on its planting and processing. Two casbene synthase gene (JcCASA163 and JcCASD168) homologues were cloned from Jatropha genome and both genes were highly expressed during seed development. In vitro functional analysis proved casbene synthase activity of JcCASA163 in converting geranylgeranyl diphosphate into casbene which has been speculated to be the precursor to PEs. A seed-specific promoter driving inverted repeats for RNAi interference targeting at either JcCASA163 or both genes could effectively down-regulate casbene synthase gene expression with concurrent marked reduction of PE level (by as much as 85 %) in seeds with no pleiotropic effects observed. Such engineered low PE in seed was heritable and co-segregated with the transgene. Our work implicated casbene synthase in Jatropha PE biosynthesis and provided evidence for casbene being the precursor for PEs. The success in reducing seed PE content through down-regulation of casbene synthase demonstrates the feasibility of intercepting PE biosynthesis in Jatropha seed to help address safety concerns on Jatropha plantation and seed processing and facilitate use of its seed protein for animal nutrition.
Assuntos
Regulação da Expressão Gênica de Plantas , Jatropha/enzimologia , Ésteres de Forbol/metabolismo , Fósforo-Oxigênio Liases/genética , Sequência de Aminoácidos , Animais , Biocombustíveis , Regulação para Baixo , Perfilação da Expressão Gênica , Engenharia Genética , Humanos , Jatropha/química , Jatropha/genética , Especificidade de Órgãos , Fósforo-Oxigênio Liases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Interferência de RNA , Sementes/química , Sementes/enzimologia , Sementes/genética , Alinhamento de SequênciaRESUMO
The recognition between disease resistance (R) genes in plants and their cognate avirulence (Avr) genes in pathogens can produce a hypersensitive response of localized programmed cell death. However, our knowledge of the early signaling events of the R gene-mediated hypersensitive response in plants remains limited. Here, we report the cloning and characterization of Xa10, a transcription activator-like (TAL) effector-dependent R gene for resistance to bacterial blight in rice (Oryza sativa). Xa10 contains a binding element for the TAL effector AvrXa10 (EBEAvrXa10) in its promoter, and AvrXa10 specifically induces Xa10 expression. Expression of Xa10 induces programmed cell death in rice, Nicotiana benthamiana, and mammalian HeLa cells. The Xa10 gene product XA10 localizes as hexamers in the endoplasmic reticulum (ER) and is associated with ER Ca(2+) depletion in plant and HeLa cells. XA10 variants that abolish programmed cell death and ER Ca(2+) depletion in N. benthamiana and HeLa cells also abolish disease resistance in rice. We propose that XA10 is an inducible, intrinsic terminator protein that triggers programmed cell death by a conserved mechanism involving disruption of the ER and cellular Ca(2+) homeostasis.
Assuntos
Apoptose/genética , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Oryza/metabolismo , Proteínas de Plantas/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , Resistência à Doença/genética , Células HeLa , Humanos , Membranas Intracelulares/metabolismo , Dados de Sequência Molecular , Oryza/citologia , Proteínas de Plantas/análise , Proteínas de Plantas/genética , Nicotiana/citologia , Nicotiana/genética , Nicotiana/metabolismoRESUMO
Increasing studies have shown that the interactions between microRNAs (miRNAs) and environmental factors (EFs) play critical roles in determining phenotypes and diseases. In this study, we revealed a number of important biological insights by analyzing and modeling of miRNA-EF interactions and their relationships with human diseases. We demonstrated that the miRNA signatures of EFs could provide new information on EFs. More importantly, we quantitatively showed that the miRNA signatures of drug/radiation could be used as indicators for evaluating the results of cancer treatments. Finally, we developed a computational model that could efficiently identify the possible relationship between EF and human diseases. Meanwhile, we provided a website (http://cmbi.hsc.pku.edu.cn/miren) for the main results of this study. This study elucidates the mechanisms of EFs, presents a framework for predicting the results of cancer treatments, and develops a model that illustrates the relationships between EFs and human diseases.
Assuntos
Doença/genética , MicroRNAs/genética , HumanosRESUMO
With the rapid accumulation of microRNA (miRNAs), a class of newly identified small noncoding RNAs, in silico inference of miRNA functions has become one of the central tasks in miRNA bioinformatics. Traditional methods have helped in the understanding of miRNAs, but they also have limitations. In this paper, we first gave a brief review for the progress of bioinformatic methods in miRNA function inference and next presented a new framework (miRUPnet) for inferring the functions of miRNAs by functional analysis of a novel dimension of miRNA network, the context of its transcription factors (TFs) in a protein-protein interaction network. This dimension represents specific biological processes initiated by TF combinations and therefore differs from traditional methods in concept. To validate the accuracy of our method, we first comprehensively mined literature-reported miRNA functions and then made a comparison with the prediction result. The results show that even using the stringent TFBS rule, our method has independently predicted 68.2% of the literature reported miRNA functions, suggesting that miRUPnet has a high accuracy. Moreover, our approach successfully predicted specific functions that could not be inferred for given miRNAs using traditional methods. More importantly, it can distinguish miRNAs from the same family, as well as those present in multiple copies that cannot be differentiated through traditional methods. This study presents a new concept and dimension for miRNA function inference. miRUPnet represents an important and novel method for inferring the function of miRNAs. miRUPnet is available at http://cmbi.bjmu.edu.cn/mirupnet.
Assuntos
Biologia Computacional/métodos , MicroRNAs/metabolismo , Transdução de Sinais/genética , Ciclo Celular/genética , Bases de Dados Genéticas , Humanos , MicroRNAs/genética , Metástase Neoplásica/genética , SoftwareRESUMO
MicroRNAs (miRNAs) are small noncoding RNAs which play essential roles in many important biological processes. Therefore, their dysfunction is associated with a variety of human diseases, including cancer. Increasing evidence shows that miRNAs can act as oncogenes or tumor suppressors, and although there is great interest in research into these cancer-associated miRNAs, little is known about them. In this study, we performed a comprehensive analysis of putative human miRNA oncogenes and tumor suppressors. We found that miRNA oncogenes and tumor suppressors clearly show different patterns in function, evolutionary rate, expression, chromosome distribution, molecule size, free energy, transcription factors, and targets. For example, miRNA oncogenes are located mainly in the amplified regions in human cancers, whereas miRNA tumor suppressors are located mainly in the deleted regions. miRNA oncogenes tend to cleave target mRNAs more frequently than miRNA tumor suppressors. These results indicate that these two types of cancer-associated miRNAs play different roles in cancer formation and development. Moreover, the patterns identified here can discriminate novel miRNA oncogenes and tumor suppressors with a high degree of accuracy. This study represents the first large-scale bioinformatic analysis of human miRNA oncogenes and tumor suppressors. Our findings provide help for not only understanding of miRNAs in cancer but also for the specific identification of novel miRNAs as miRNA oncogenes and tumor suppressors. In addition, the data presented in this study will be valuable for the study of both miRNAs and cancer.
Assuntos
MicroRNAs/metabolismo , Neoplasias/genética , Oncogenes , Evolução Molecular , Regulação da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , Neoplasias/metabolismoRESUMO
MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and are therefore important cellular components. As is true for protein-coding genes, the transcription of miRNAs is regulated by transcription factors (TFs), an important class of gene regulators that act at the transcriptional level. The correct regulation of miRNAs by TFs is critical, and increasing evidence indicates that aberrant regulation of miRNAs by TFs can cause phenotypic variations and diseases. Therefore, a TF-miRNA regulation database would be helpful for understanding the mechanisms by which TFs regulate miRNAs and understanding their contribution to diseases. In this study, we manually surveyed approximately 5000 reports in the literature and identified 243 TF-miRNA regulatory relationships, which were supported experimentally from 86 publications. We used these data to build a TF-miRNA regulatory database (TransmiR, http://cmbi.bjmu.edu.cn/transmir), which contains 82 TFs and 100 miRNAs with 243 regulatory pairs between TFs and miRNAs. In addition, we included references to the published literature (PubMed ID) information about the organism in which the relationship was found, whether the TFs and miRNAs are involved with tumors, miRNA function annotation and miRNA-associated disease annotation. TransmiR provides a user-friendly interface by which interested parties can easily retrieve TF-miRNA regulatory pairs by searching for either a miRNA or a TF.
Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Bases de Dados de Ácidos Nucleicos , Redes Reguladoras de Genes , MicroRNAs/genética , Fatores de Transcrição/genética , Algoritmos , Animais , Biologia Computacional/tendências , Bases de Dados de Proteínas , Humanos , Armazenamento e Recuperação da Informação/métodos , Internet , MicroRNAs/metabolismo , Fenótipo , PubMed , Software , Fatores de Transcrição/químicaRESUMO
As the second enzyme of the non-mevalonate terpenoid pathway for isopentenyl diphosphate biosynthesis, DXP reductoisomerase (DXR, EC: 1.1.1.267) catalyzes a committed step of the MEP pathway for camptothecin (CPT) biosynthesis. In order to understand more about the role of DXR involved in the CPT biosynthesis at the molecular level, the full-length DXR cDNA sequence (designated as CaDXR) was isolated and characterized for the first time from a medicinal Nyssaceae plant species, Camptotheca acuminata. The full-length cDNA of CaDXR was 1823 bp containing a 1416 bp open reading frame (ORF) encoding a polypeptide of 472 amino acids. Comparative and bioinformatic analyses revealed that CaDXR showed extensive homology with DXRs from other plant species and contained a conserved transit peptide for plastids, an extended Pro-rich region and a highly conserved NADPH binding motif in its N-terminal region owned by all plant DXRs. Phylogenetic analysis indicated that CaDXR was more ancient than other plant DXRs. Tissue expression pattern analysis revealed that CaDXR expressed strongly in stem, weak in leaf and root. CaDXR was found to be an elicitor-responsive gene, which could be induced by exogenous elicitor of methyl jasmonate. The functional color complementation assay indicated that CaDXR could accelerate the biosynthesis of carotenoids in the Escherichia coli transformant, demonstrating that DXP reductoisomerase plays an influential step in isoprenoid biosynthesis.
Assuntos
Aldose-Cetose Isomerases/genética , Camptotheca/genética , Perfilação da Expressão Gênica , Genes de Plantas , Complexos Multienzimáticos/genética , Oxirredutases/genética , Aldose-Cetose Isomerases/química , Sequência de Aminoácidos , Sequência de Bases , Camptotheca/enzimologia , Clonagem Molecular , DNA Complementar , Escherichia coli/genética , Dados de Sequência Molecular , Complexos Multienzimáticos/química , Oxirredutases/química , Filogenia , Reação em Cadeia da Polimerase , RNA de Plantas/genética , RNA de Plantas/isolamento & purificação , Homologia de Sequência de AminoácidosRESUMO
GbERF belongs to the ERF (ethylene responsive factor) family of transcription factors and regulates the GCC-box containing pathogen-related (PR) genes in the ethylene signal transduction pathway. To study the function of GbERF in the process of biotic stress, transgenic tobacco plants expressing GbERF were generated. Overexpression of GbERF did not change transgenic plant's phenotype and endogenous ethylene level. However, the expression profile of some ethylene-inducible GCC-box and non-GCC-box containing genes was altered, such as PR1b, PR2, PR3, PR4, Osmotin, CHN50, ACC oxidase and ACC synthase genes. These data indicate that the cotton GbERF could act as a transcriptional activator or repressor to regulate the differential expression of ethylene-inducible genes via GCC and non-GCC cis-elements. Moreover, the constitutive expression of GbERF in transgenic tobacco enhanced the plant's resistance to Pseudomonas syringae pv tabaci infection. In conclusion, GbERF mediates the expression of a wide array of PR and ethylene-responsive genes and plays an important role in the plant's response to biotic stress.
Assuntos
Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Nicotiana , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Pseudomonas syringae/patogenicidade , Fatores de Transcrição/metabolismo , Sequência de Bases , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Proteínas de Plantas/genética , Sementes/crescimento & desenvolvimento , Transdução de Sinais/fisiologia , Nicotiana/genética , Nicotiana/metabolismo , Nicotiana/microbiologia , Fatores de Transcrição/genética , Transformação GenéticaRESUMO
Class III homeodomain-leucine zipper (HD-Zip III) genes are important plant-specific transcription factors which have key roles in different stages of vascular and interfascicular fiber differentiation. A novel HD-Zip III gene, designated GbHB1, was isolated by suppression subtraction hybridization and RACE (rapid amplification of cDNA ends) from Gossypium barbadense (sea-island cotton). The GbHB1 cDNA has a total length of 3061 bp with an open reading frame of 2508 bp, encoding a predicated polypeptide of 836 amino acids with a molecular weight of 91.6 kDa and a calculated pI of 5.93. The putative polypeptide of GbHB1 is structurally characterized by a homeodomain positioned adjacent to a leucine zipper domain, which shares high identity with other reported HD-Zip III domains. DNA gel blotting analysis shows that GbHB1 is a low-copy gene. Organ expression pattern analysis reveals that GbHB1 expressed highly in ovule and stem, followed by in root, and low in leaf and cotyledon. The result suggests that GbHB1 may play a regulatory role in cotton interfascicular fiber development.