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1.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
2.
BMC Bioinformatics ; 20(1): 414, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387525

RESUMO

BACKGROUND: R-loops are three-stranded nucleic acid structures that usually form during transcription and that may lead to gene regulation or genome instability. DRIP (DNA:RNA Immunoprecipitation)-seq techniques are widely used to map R-loops genome-wide providing insights into R-loop biology. However, annotation of DRIP-seq peaks to genes can be a tricky step, due to the lack of strand information when using the common basic DRIP technique. RESULTS: Here, we introduce DRIP-seq Optimized Peak Annotator (DROPA), a new tool for gene annotation of R-loop peaks based on gene expression information. DROPA allows a full customization of annotation options, ranging from the choice of reference datasets to gene feature definitions. DROPA allows to assign R-loop peaks to the DNA template strand in gene body with a false positive rate of less than 7%. A comparison of DROPA performance with three widely used annotation tools show that it identifies less false positive annotations than the others. CONCLUSIONS: DROPA is a fully customizable peak-annotation tool optimized for co-transcriptional DRIP-seq peaks, which allows a finest gene annotation based on gene expression information. Its output can easily be integrated into pipelines to perform downstream analyses, while useful and informative summary plots and statistical enrichment tests can be produced.


Assuntos
DNA/metabolismo , Imunoprecipitação , Anotação de Sequência Molecular , RNA/metabolismo , Software , Sequência de Bases , DNA/genética , Regulação da Expressão Gênica , RNA/genética
3.
Medicine (Baltimore) ; 98(34): e16922, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441876

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in cervical cancer remains largely unknown. This study aimed to describe the regulatory mechanisms in cervical cancer. METHODS: We downloaded the circRNAs expression profiles from Gene Expression Omnibus database, and RNAs expression profiles from The Cancer Genome Atlas database. We established a circRNA-miRNA-mRNA and circRNA-miRNA-hubgene network. The interactions between proteins were analyzed using the STRING database and hubgenes were identified using MCODE plugin. Then, we conducted a circRNA-miRNA-hubgenes regulatory module. Functional and pathway enrichment analyses were conducted using R packages "Clusterprofile". RESULTS: Six circRNAs, 15 miRNAs, and 158 mRNAs were identified to construct the ceRNA network of cervical cancer. PPI (protein-protein interaction) network and module analysis identified 7 hubgenes. Then, a circRNA-miRNA-hubgene subnetwork was constructed based on the 1 DEcircRNAs, 3 DEmiRNAs, and 3 DEmRNAs. The KEGG pathway analysis indicated DEmRNAs are involved in progesterone-mediated oocyte maturation, cell cycle, and oocyte meiosis. CONCLUSION: These ceRNAs are critical in the pathogenesis of cervical and may serve as future therapeutic biomarkers.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , RNA/genética , Neoplasias do Colo do Útero/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Mapas de Interação de Proteínas , RNA/metabolismo
4.
BMC Bioinformatics ; 20(1): 421, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409274

RESUMO

BACKGROUND: Ultra-fast pseudo-alignment approaches are the tool of choice in transcript-level RNA sequencing (RNA-seq) analyses. Unfortunately, these methods couple the tasks of pseudo-alignment and transcript quantification. This coupling precludes the direct usage of pseudo-alignment to other expression analyses, including alternative splicing or differential gene expression analysis, without including a non-essential transcript quantification step. RESULTS: In this paper, we introduce a transcriptome segmentation approach to decouple these two tasks. We propose an efficient algorithm to generate maximal disjoint segments given a transcriptome reference library on which ultra-fast pseudo-alignment can be used to produce per-sample segment counts. We show how to apply these maximally unambiguous count statistics in two specific expression analyses - alternative splicing and gene differential expression - without the need of a transcript quantification step. Our experiments based on simulated and experimental data showed that the use of segment counts, like other methods that rely on local coverage statistics, provides an advantage over approaches that rely on transcript quantification in detecting and correctly estimating local splicing in the case of incomplete transcript annotations. CONCLUSIONS: The transcriptome segmentation approach implemented in Yanagi exploits the computational and space efficiency of pseudo-alignment approaches. It significantly expands their applicability and interpretability in a variety of RNA-seq analyses by providing the means to model and capture local coverage variation in these analyses.


Assuntos
Algoritmos , Transcriptoma , Processamento Alternativo , Animais , Área Sob a Curva , Drosophila/genética , Humanos , RNA/química , RNA/metabolismo , Curva ROC , Análise de Sequência de RNA
5.
BMC Bioinformatics ; 20(1): 418, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409293

RESUMO

BACKGROUND: Standard RNAseq methods using bulk RNA and recent single-cell RNAseq methods use DNA barcodes to identify samples and cells, and the barcoded cDNAs are pooled into a library pool before high throughput sequencing. In cases of single-cell and low-input RNAseq methods, the library is further amplified by PCR after the pooling. Preparation of hundreds or more samples for a large study often requires multiple library pools. However, sometimes correlation between expression profiles among the libraries is low and batch effect biases make integration of data between library pools difficult. RESULTS: We investigated 166 technical replicates in 14 RNAseq libraries made using the STRT method. The patterns of the library biases differed by genes, and uneven library yields were associated with library biases. The former bias was corrected using the NBGLM-LBC algorithm, which we present in the current study. The latter bias could not be corrected directly, but could be solved by omitting libraries with particularly low yields. A simulation experiment suggested that the library bias correction using NBGLM-LBC requires a consistent sample layout. The NBGLM-LBC correction method was applied to an expression profile for a cohort study of childhood acute respiratory illness, and the library biases were resolved. CONCLUSIONS: The R source code for the library bias correction named NBGLM-LBC is available at https://shka.github.io/NBGLM-LBC and https://shka.bitbucket.io/NBGLM-LBC . This method is applicable to correct the library biases in various studies that use highly multiplexed sequencing-based profiling methods with a consistent sample layout with samples to be compared (e.g., "cases" and "controls") equally distributed in each library.


Assuntos
Biblioteca Gênica , Análise de Sequência de RNA/métodos , Transcriptoma , Linhagem Celular , Análise por Conglomerados , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Análise de Componente Principal , RNA/química , RNA/metabolismo , Interface Usuário-Computador
6.
Nat Commun ; 10(1): 2909, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266957

RESUMO

Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show that protein disorder is abundant in protein/RNA granules and lysine is enriched in disordered regions of proteins in P-bodies compared to the entire human disordered proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates that are more dynamic and differ at the molecular level from arginine/RNA-coacervates. Consistent with the ability of lysine to drive phase separation, lysine-rich variants of the Alzheimer's disease-linked protein tau undergo coacervation with RNA in vitro and bind to stress granules in cells. Acetylation of lysine reverses liquid-liquid phase separation and reduces colocalization of tau with stress granules. Our study establishes lysine as an important regulator of cellular condensation.


Assuntos
Lisina/metabolismo , RNA/química , RNA/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo , Acetilação , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Linhagem Celular , Grânulos Citoplasmáticos/genética , Grânulos Citoplasmáticos/metabolismo , Humanos , Lisina/química , Lisina/genética , RNA/genética , Proteínas tau/genética
7.
Adv Exp Med Biol ; 1157: 85-98, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31342438

RESUMO

RNA degradation is considered a critical posttranscriptional regulatory checkpoint, maintaining the correct functioning of organisms. When a specific RNA transcript is no longer required in the cell, it is signaled for degradation through a number of highly regulated steps. Ribonucleases (or simply RNases) are key enzymes involved in the control of RNA stability. These enzymes can perform the RNA degradation alone or cooperate with other proteins in RNA degradation complexes. Important findings over the last years have shed light into eukaryotic RNA degradation by members of the RNase II/RNB family of enzymes. DIS3 enzyme belongs to this family and represents one of the catalytic subunits of the multiprotein complex exosome. This RNase has a diverse range of functions, mainly within nuclear RNA metabolism. Humans encode two other DIS3-like enzymes: DIS3L (DIS3L1) and DIS3L2. DIS3L1 also acts in association with the exosome but is strictly cytoplasmic. In contrast, DIS3L2 acts independently of the exosome and shows a distinctive preference for uridylated RNAs. These enzymes have been shown to be involved in important cellular processes, such as mitotic control, and associated with human disorders like cancer. This review shows how the impairment of function of each of these enzymes is implicated in human disease.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo , Neoplasias , RNA , Ribonucleases , Endorribonucleases , Exorribonucleases , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos , Humanos , Neoplasias/fisiopatologia , RNA/metabolismo , Estabilidade de RNA , Ribonucleases/metabolismo
8.
Chem Commun (Camb) ; 55(58): 8402-8405, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31257385

RESUMO

A proof-of-principle for the application of hemi-indigo derivatives as RNA binders with photocontrollable fluorescence is presented. The photoswitch binds to the human immunodeficiency virus type 1 (HIV-1) RNA with a significant light-up effect. The fluorescence of the RNA-bound ligand can be reversibly switched ON and OFF by light without destroying the ligand-RNA associates.


Assuntos
Corantes Fluorescentes/metabolismo , HIV-1/genética , Indóis/metabolismo , RNA/metabolismo , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Indóis/química , Indóis/efeitos da radiação , Ligantes , Luz , Estudo de Prova de Conceito , RNA/genética , Elementos de Resposta , Estereoisomerismo
9.
Zool Res ; 40(4): 293-304, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31271004

RESUMO

Divergence of gene expression and alternative splicing is a crucial driving force in the evolution of species; to date, however the molecular mechanism remains unclear. Hybrids of closely related species provide a suitable model to analyze allele-specific expression (ASE) and allele-specific alternative splicing (ASS). Analysis of ASE and ASS can uncover the differences in cis-regulatory elements between closely related species, while eliminating interference of trans-regulatory elements. Here, we provide a detailed characterization of ASE and ASS from 19 and 10 transcriptome datasets across five tissues from reciprocal-cross hybrids of horse×donkey (mule/hinny) and cattle×yak (dzo), respectively. Results showed that 4.8%-8.7% and 10.8%-16.7% of genes exhibited ASE and ASS, respectively. Notably, lncRNAs and pseudogenes were more likely to show ASE than protein-coding genes. In addition, genes showing ASE and ASS in mule/hinny were found to be involved in the regulation of muscle strength, whereas those of dzo were involved in high-altitude adaptation. In conclusion, our study demonstrated that exploration of genes showing ASE and ASS in hybrids of closely related species is feasible for species evolution research.


Assuntos
Alelos , Processamento Alternativo , Bovinos/genética , Equidae/genética , Hibridização Genética/genética , Animais , Sequência de Bases , Regulação da Expressão Gênica , RNA/genética , RNA/metabolismo
10.
BMC Bioinformatics ; 20(1): 372, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266442

RESUMO

BACKGROUND: The studies of functions of circular RNAs (circRNAs) are heavily focused on the regulation of gene expression through interactions with multiple miRNAs. However, the number of predicted target genes is typically overwhelming due to the synergistic complexity caused by two factors ─ the binding of multiple miRNAs to a circRNA and the existence of multiple targets for each miRNA. Analysis of common targets (ACT) was designed to facilitate the identification of potential circRNA targets. RESULTS: We demonstrated the feasibility of the proposed feature/measurement to assess which genes are more likely to be regulated by circRNAs with given sequences by calculating the level of co-regulation by multiple miRNAs. The web service is made freely available at http://lab-x-omics.nchu.edu.tw/ACT_Server . CONCLUSIONS: ACT allows users to identify potential circRNA-regulated genes and their associated pathways for further investigation.


Assuntos
RNA/metabolismo , Interface Usuário-Computador , Animais , Metabolismo Energético/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética
11.
BMC Bioinformatics ; 20(1): 373, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269893

RESUMO

BACKGROUND: RNA molecules play many crucial roles in living systems. The spatial complexity that exists in RNA structures determines their cellular functions. Therefore, understanding RNA folding conformations, in particular, RNA secondary structures, is critical for elucidating biological functions. Existing literature has focused on RNA design as either an RNA structure prediction problem or an RNA inverse folding problem where free energy has played a key role. RESULTS: In this research, we propose a Positive-Unlabeled data- driven framework termed ENTRNA. Other than free energy and commonly studied sequence and structural features, we propose a new feature, Sequence Segment Entropy (SSE), to measure the diversity of RNA sequences. ENTRNA is trained and cross-validated using 1024 pseudoknot-free RNAs and 1060 pseudoknotted RNAs from the RNASTRAND database respectively. To test the robustness of the ENTRNA, the models are further blind tested on 206 pseudoknot-free and 93 pseudoknotted RNAs from the PDB database. For pseudoknot-free RNAs, ENTRNA has 86.5% sensitivity on the training dataset and 80.6% sensitivity on the testing dataset. For pseudoknotted RNAs, ENTRNA shows 81.5% sensitivity on the training dataset and 71.0% on the testing dataset. To test the applicability of ENTRNA to long structural-complex RNA, we collect 5 laboratory synthetic RNAs ranging from 1618 to 1790 nucleotides. ENTRNA is able to predict the foldability of 4 RNAs. CONCLUSION: In this article, we reformulate the RNA design problem as a foldability prediction problem which is to predict the likelihood of the co-existence of a sequence-structure pair. This new construct has the potential for both RNA structure prediction and the inverse folding problem. In addition, this new construct enables us to explore data-driven approaches in RNA research.


Assuntos
Algoritmos , RNA/metabolismo , Bases de Dados Genéticas , RNA/química , Dobramento de RNA , Termodinâmica
12.
BMC Bioinformatics ; 20(1): 394, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311497

RESUMO

BACKGROUND: High-dimensional data of discrete and skewed nature is commonly encountered in high-throughput sequencing studies. Analyzing the network itself or the interplay between genes in this type of data continues to present many challenges. As data visualization techniques become cumbersome for higher dimensions and unconvincing when there is no clear separation between homogeneous subgroups within the data, cluster analysis provides an intuitive alternative. The aim of applying mixture model-based clustering in this context is to discover groups of co-expressed genes, which can shed light on biological functions and pathways of gene products. RESULTS: A mixture of multivariate Poisson-log normal (MPLN) model is developed for clustering of high-throughput transcriptome sequencing data. Parameter estimation is carried out using a Markov chain Monte Carlo expectation-maximization (MCMC-EM) algorithm, and information criteria are used for model selection. CONCLUSIONS: The mixture of MPLN model is able to fit a wide range of correlation and overdispersion situations, and is suited for modeling multivariate count data from RNA sequencing studies. All scripts used for implementing the method can be found at https://github.com/anjalisilva/MPLNClust .


Assuntos
Algoritmos , RNA/química , Análise por Conglomerados , Sequenciamento de Nucleotídeos em Larga Escala , Cadeias de Markov , Modelos Teóricos , Método de Monte Carlo , RNA/genética , RNA/metabolismo , Análise de Sequência de RNA , Interface Usuário-Computador
13.
Toxicol Lett ; 314: 89-97, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325635

RESUMO

Ethanol is a key factor in the pathogenesis of alcoholic liver disease (ALD), commonly characterized as liver inflammation. Recently, circular (circ)RNAs have emerged as important targets to cure liver diseases. However, there are no studies investigating the role of circ_1639 in reducing inflammatory responses in ALD. In this study, we found that circ_1639 was upregulated in Kupffer cells from the livers of alcohol fed mice. We hypothesized that circ_1639 inhibition is a potential novel therapy for treating ALD. To test this hypothesis, RAW 264.7 cells were treated with ethanol and transfected with circ_1639 overexpression or knockdown plasmids. We present western blotting, qRT-PCR, and ELISA data that suggest that circ_1639 is a proinflammatory factor in the liver and is involved in the activation of the NF-κB signaling pathway. Using luciferase reporter assay, we confirmed that microRNA (miR)-122 is a target gene of circ_1639. We also show that TNFRSF13C is a key regulator of RAW 264.7 cell activation, and acts as a downstream target for miR-122. In summary, our results suggest that inhibition of circ_1639 expression may reduce inflammatory responses in ALD.


Assuntos
Mediadores da Inflamação/metabolismo , Hepatopatias Alcoólicas/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , RNA/metabolismo , Animais , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Macrófagos do Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células RAW 264.7 , RNA/genética , Transdução de Sinais
14.
BMC Bioinformatics ; 20(1): 388, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299886

RESUMO

BACKGROUND: Single-cell RNA-sequencing technologies provide a powerful tool for systematic dissection of cellular heterogeneity. However, the prevalence of dropout events imposes complications during data analysis and, despite numerous efforts from the community, this challenge has yet to be solved. RESULTS: Here we present a computational method, called RESCUE, to mitigate the dropout problem by imputing gene expression levels using information from other cells with similar patterns. Unlike existing methods, we use an ensemble-based approach to minimize the feature selection bias on imputation. By comparative analysis of simulated and real single-cell RNA-seq datasets, we show that RESCUE outperforms existing methods in terms of imputation accuracy which leads to more precise cell-type identification. CONCLUSIONS: Taken together, these results suggest that RESCUE is a useful tool for mitigating dropouts in single-cell RNA-seq data. RESCUE is implemented in R and available at https://github.com/seasamgo/rescue .


Assuntos
Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Software , Viés , Células/metabolismo , Simulação por Computador , Regulação da Expressão Gênica , Humanos , RNA/genética , RNA/metabolismo
15.
Life Sci ; 231: 116660, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319086

RESUMO

Hepatocellular carcinoma (HCC), a leading cause of cancer-related death with high invasive and metastatic potential, has a low survival rate. To improve the survival and quality of life in HCC patients, it is urgently needed to explore novel biomarkers for early diagnosis and prognosis of HCC, as well as therapeutic strategies. Circular RNAs (circRNAs) are a class of highly conserved, stable and abundant non-coding RNAs (ncRNAs) that can regulate gene expression at transcriptional or post-transcriptional levels. Recently, some circRNAs are identified to be potential biomarkers for HCC diagnosis and prognosis. Furthermore, some circRNAs are found to play oncogenic or suppressive roles in HCC progression by regulating various biological processes, including cell proliferation, migration, invasion and metastasis, epithelial-mesenchymal transition (EMT), as well as apoptosis. In this review, we summarize recent findings of deregulated circRNAs, their functions and molecular mechanisms in HCC, and discuss their potential roles as diagnostic biomarkers, prognostic biomarkers, as well as therapeutic targets for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Invasividade Neoplásica , Prognóstico , RNA/genética
16.
Cancer Sci ; 110(9): 2960-2972, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301086

RESUMO

In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin-coupled microRNA capture were carried out to investigate the Ago2-dependent interaction of circCRIM1 and microRNA (miR)-93/miR-182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well-known tumor suppressor, by sponging miR-93 and miR-182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , RNA/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , RNA/genética , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Chem Pharm Bull (Tokyo) ; 67(6): 505-518, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155555

RESUMO

Nucleic acid therapeutics such as antisense and small interfering RNA (siRNA) have attracted increasing attention as innovative medicines that interfere with and/or modify gene expression systems. We have developed new functional oligonucleotides that can target DNA and RNA with high efficiency and selectivity. This review summarizes our achievements, including (1) the formation of non-natural triplex DNA for sequence-specific inhibition of transcription; (2) artificial receptor molecules for 8-oxidized-guanosine nucleosides; and (3) reactive oligonucleotides with a cross-linking agent or a functionality-transfer nucleoside for RNA pinpoint modification.


Assuntos
DNA/química , RNA/química , Reagentes para Ligações Cruzadas/química , DNA/metabolismo , DNA/farmacologia , Humanos , Nucleosídeos/análogos & derivados , Nucleosídeos/farmacologia , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Polietilenoglicóis/química , RNA/metabolismo , Telomerase/genética , Telomerase/metabolismo , Transcrição Genética/efeitos dos fármacos
18.
Nat Commun ; 10(1): 2550, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186410

RESUMO

The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m5C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m5C deposition into the abundant non-coding vault RNA VTRNA1.1. Methylation of cytosine 69 in VTRNA1.1 occurs frequently in human cells, is exclusively mediated by NSUN2, and determines the processing of VTRNA1.1 into small-vault RNAs (svRNAs). We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein that counteracts VTRNA1.1 processing by binding the non-methylated form with higher affinity. Both NSUN2 and SRSF2 orchestrate the production of distinct svRNAs. Finally, we discover a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for m5C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.


Assuntos
5-Metilcitosina/metabolismo , Metilação de DNA , Células Epidérmicas/citologia , Metiltransferases/metabolismo , RNA/metabolismo , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Diferenciação Celular , Linhagem Celular , Citosina/metabolismo , Células Epidérmicas/metabolismo , Células HEK293 , Células HeLa , Células-Tronco Embrionárias Humanas/citologia , Humanos , Metiltransferases/genética , RNA/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo
19.
Chem Biol Interact ; 309: 108675, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31150632

RESUMO

Liver fibrosis is a progression of chronic liver disease with lacks effective therapies at present. Schisandrin B (Sch B), a bioactive compound extracted from the traditional Chinese medicine Schisandra chinensis, was reported to benefit liver diseases. This study aimed to investigate the therapeutic effects and molecular mechanisms of Sch B against CCl4-induced liver fibrosis in rats. RNA sequencing and transcriptome analysis were performed collaboratively, including analysis of differential gene expression, gene ontology (GO) analysis, pathway analysis and pathway-act-network analysis. The results demonstrated that Sch B effectively alleviated CCl4-induced liver damage and fibrosis in rats, as evidenced by improved liver function and decreased extracellular matrix deposition. Furthermore, 4440 (1878 up-regulated, 2562 down-regulated) genes in the model group versus (vs) normal group, 4243 (2584 up-regulated, 1659 down-regulated) genes in Sch B-treated group vs model group were identified as differentially expressed genes (DEGs). Subsequently, GO analysis revealed that DEGs were mainly enriched in metabolism, oxidation-reduction, endoplasmic reticulum stress and apoptosis-related biological processes. Pathway analysis suggested that Sch B up-regulated cytochrome P450 drug metabolism, PPAR signaling pathways, and down-regulated glutathione metabolism pathways. In addition, the regulatory patterns of Sch B on key genes and pathways were also confirmed. In conclusion, our study demonstrated Sch B alleviated CCl4-induced liver fibrosis by multiple modulatory mechanisms, which provide new clues for further pharmacological study of Sch B.


Assuntos
Lignanas/farmacologia , Cirrose Hepática/patologia , Fígado/metabolismo , Compostos Policíclicos/farmacologia , Transcriptoma , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Lignanas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Compostos Policíclicos/química , Compostos Policíclicos/uso terapêutico , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Ratos , Ratos Wistar , Schisandra/química , Schisandra/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
20.
Nat Commun ; 10(1): 2851, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253786

RESUMO

Male and female brains differ significantly in both health and disease, and yet the female brain has been understudied. Sex-hormone fluctuations make the female brain particularly dynamic and are likely to confer female-specific risks for neuropsychiatric disorders. The molecular mechanisms underlying the dynamic nature of the female brain structure and function are unknown. Here we show that neuronal chromatin organization in the female ventral hippocampus of mouse fluctuates with the oestrous cycle. We find chromatin organizational changes associated with the transcriptional activity of genes important for neuronal function and behaviour. We link these chromatin dynamics to variation in anxiety-related behaviour and brain structure. Our findings implicate an immediate-early gene product, Egr1, as part of the mechanism mediating oestrous cycle-dependent chromatin and transcriptional changes. This study reveals extreme, sex-specific dynamism of the neuronal epigenome, and establishes a foundation for the development of sex-specific treatments for disorders such as anxiety and depression.


Assuntos
Encéfalo/fisiologia , Cromatina/fisiologia , Ciclo Estral/fisiologia , Neurônios/fisiologia , Animais , Comportamento Animal , Encéfalo/citologia , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Epigenômica , Estradiol/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Progesterona/metabolismo , Ligação Proteica , RNA/genética , RNA/metabolismo
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