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1.
FASEB J ; 35(2): e21330, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33417289

RESUMO

Epilepsy is a common brain disorder, repeated seizures of epilepsy may lead to a series of brain pathological changes such as neuronal or glial damage. However, whether circular RNAs are involved in neuronal injury during epilepsy is not fully understood. Here, we screened circIgf1r in the status epilepticus model through circRNA sequencing, and found that it was upregulated after the status epilepticus model through QPCR analysis. Astrocytes polarizing toward neurotoxic A1 phenotype and neurons loss were observed after status epilepticus. Through injecting circIgf1r siRNA into the lateral ventricle, it was found that knocking down circIgf1r in vivo would induce the polarization of astrocytes to phenotype A2 and reduce neuronal loss. The results in vitro further confirmed that inhibiting the expression of circIgf1r in astrocytes could protect neurons by converting reactive astrocytes from A1 to the protective A2. In addition, knocking down circIgf1r in astrocytes could functionally promote astrocyte autophagy and relieve the destruction of 4-AP-induced autophagy flux. In terms of mechanism, circIgf1r promoted the polarization of astrocytes to phenotype A1 by inhibiting autophagy. Taken together, our results reveal circIgf1r may serve as a potential target for the prevention and treatment of neuron damage after epilepsy.

2.
Medicine (Baltimore) ; 99(31): e21542, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756208

RESUMO

BACKGROUND: Chronic nonspecific low back pain (CNLBP) has become a major global public health problem. Its high incidence rate and high disability rate are so damaging both to individuals and communities. At present, many countries' clinical guidelines recommend exercise therapy. Breath therapy is one of the exercise therapies, playing an important role in exercise therapy. Some studies have shown that breath therapy has a considerable therapeutic effect on low back pain, but there is no specific conclusion. The aim of our study is to answer the question: if breath therapy is effective and safe for CNLBP? METHODS: The following databases will be searched: English databases (including Web of Science, the Cochrane Library (Central), EMBASE, MEDLINE, Allied and Alternative Medicine) and Chinese databases (including Chinese National Knowledge Infrastructure, Wanfang data and Chinese Scientific Journals Database [VIP]). The literature search will be constructed around search terms for breath therapy, search terms for chronic nonspecific low back pain and search terms for randomized controlled trials. The primary outcomes were related to duration, intensity, attack frequency of pain, and the secondary outcomes were related to physical function, quality of life, and adverse events related to interventions. Endnote software 9.1 will be applied in selecting study, Review Manager software 5.3 will be applied in analyzing and synthesizing. RESULTS: The results will provide evidence to judge whether breath therapy is effective and safe for CNLBP. CONCLUSION: Our research will provide reliable evidence of breath therapy for CNLBP. REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42020156340.


Assuntos
Terapia por Exercício/métodos , Dor Lombar/terapia , Doença Crônica , Terapia por Exercício/efeitos adversos , Humanos , Desempenho Físico Funcional , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
3.
Mol Cancer ; 19(1): 128, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32838810

RESUMO

BACKGROUND: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. METHOD: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. RESULTS: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. CONCLUSION: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

4.
Food Chem Toxicol ; 140: 111279, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199975

RESUMO

Prenatal caffeine exposure (PCE) induces developmental toxicity of multi-organ and susceptibility to multi-disease in offspring. However, the effects of PCE on osteoarthritis susceptibility in adult offspring and its intrauterine programming mechanism remain to be further investigated. Here, we found that PCE induced susceptibility to osteoarthritis in male adult offspring rats, which was related to the inhibited function of cartilage matrix synthesis from fetuses to adults. Meanwhile, PCE consistently downregulated the H3K9ac and expression levels of transforming growth factor ß receptor 1 (TGFßR1), and then blocked TGFß signaling pathway, which contributed to the suppressed cartilage matrix synthesis. Moreover, the high level of corticosterone caused by PCE reduced the H3K9ac level on TGFßR1 promoter region through acting on glucocorticoids receptor (GR) and recruiting histone deacetylase 2 (HDAC2) into the nucleus of fetal chondrocytes. Taken together, PCE induced osteoarthritis susceptibility in male adult offspring rats, which was attributed to the low-functional programming of TGFßR1 induced by corticosterone via GR/HDAC2 signaling.

5.
Pathol Res Pract ; 215(10): 152575, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387807

RESUMO

The important role of LncRNA in the development of breast cancer is attracting more and more attention. In the previous study, we found that the expression level of LncRNA SNHG6 in breast cancer tissues and cells was significantly increased, but its mechanism in the development of breast cancer was still unclear. Our study found that knockdown of SNHG6 significantly inhibited the proliferation, migration and invasion of breast cancer cells MCF-7 and MDA-MB-231 cells. Further study showed that knockdown of SNHG6 significantly inhibited the expression level of VASP. More importantly, SNHG6 and VASP both can bind directly to miR-26a, suggesting that SNHG6 could act as a ceRNA to sponge miR-26a, thereby promoting the expression of VASP, which leading to activated proliferation, migration and invasion of breast cancer cells. Taken together, this study revealed the important role of the SNHG6/miR-26a/VASP regulatory network in the development of breast cancer, and provided a reference for exploring new pathogenesis and biomarkers of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Invasividade Neoplásica/genética , Fosfoproteínas/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Inativação Gênica , Humanos , Invasividade Neoplásica/patologia , RNA Longo não Codificante/genética
6.
Nat Cell Biol ; 21(5): 651-661, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31036937

RESUMO

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N6-methyladenosine (m6A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m6A in human tissues, we generated 21 whole-transcriptome m6A methylomes across major fetal tissues using m6A sequencing. These data reveal dynamic m6A methylation, identify large numbers of tissue differential m6A modifications and indicate that m6A is positively correlated with gene expression homeostasis. We also report m6A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m6A. Tissue m6A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m6A modifications. Finally, we find that m6A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m6A. Our data indicate that m6A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m6A in human development and disease.


Assuntos
Adenosina/análogos & derivados , Elementos Facilitadores Genéticos , Desenvolvimento Fetal/genética , Feto , Adenosina/genética , Epigenômica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Transcriptoma/genética
7.
Mol Cancer ; 18(1): 35, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849979

RESUMO

Circular RNA (circRNA) is a group of RNA families generated by RNA circularization, which was discovered ubiquitously across different cancers. However, the internal structure of circRNA is difficult to determine due to alternative splicing that occurs in its exons and introns. Furthermore, cancer-specific alternative splicing of circRNA is less likely to be identified. Here, we proposed a de novo algorithm, CircSplice, that could identify internal alternative splicing in circRNA and compare differential circRNA splicing events between different conditions ( http://gb.whu.edu.cn/CircSplice or https://github.com/GeneFeng/CircSplice ). By applying CircSplice in clear cell renal cell carcinoma and bladder cancer, we detected 4498 and 2977 circRNA alternative splicing (circ-AS) events in the two datasets respectively and confirmed the expression of circ-AS events by RT-PCR. We further inspected the distributions and patterns of circ-AS in cancer and adjacent normal tissues. To further understand the potential functions of cancer-specific circ-AS, we classified those events into tumor suppressors and oncogenes and performed pathway enrichment analysis. This study is the first comprehensive view of cancer-specific circRNA alternative splicing, which could contribute significantly to regulation and functional research of circRNAs in cancers.


Assuntos
Algoritmos , Processamento Alternativo , Carcinoma de Células Renais/genética , Genoma Humano , RNA Neoplásico/genética , RNA/genética , Neoplasias da Bexiga Urinária/genética , Bases de Dados Factuais , Humanos , Neoplasias Renais/genética , RNA Circular
8.
J Cell Biochem ; 120(6): 10613-10624, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30809850

RESUMO

Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are involved in a variety of physiological and pathological processes. We analyzed 11 data sets from Gene Expression Omnibus Database and found that MMP7 and MMP15 were highly expressed in multiple carcinomas. GSE13204 showed that MMP7 and MMP15 were overexpressed in acute myeloid leukemia (AML) patients. The Cancer Genome Atlas data set exhibited that high expression of MMP7 or MMP15 in bone marrow (BM) of AML patients predicted poor overall survival. The χ 2 test results indicated that high expression level of MMP7 and MMP15 were correlated with high-risk stratification and high BM blast cell percentage in AML patients. To confirm these findings, we performed reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and found that MMP7 and MMP15 were highly expressed in three AML cell lines. Further study showed that MMP7 and MMP15 were highly expressed both in BM and peripheral blood in collected AML samples compared with healthy individuals. Additionally, long noncoding RNA (lncRNA) microarray of BM samples of AML patients revealed that multiple lncRNAs were correlated with MMP7 and MMP15, suggesting that lncRNAs might be involved in the pathogenesis of AML via modulating MMPs. In conclusion, our study uncovers the potential roles of MMP7 and MMP15 in the prognosis of AML.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Metaloproteinase 15 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Adolescente , Estudos de Casos e Controles , Linhagem Celular Tumoral , Criança , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas , RNA Longo não Codificante/genética
9.
Cells ; 8(2)2019 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-30781586

RESUMO

N6-methyladenosine (m6A) has been identified in various biological processes and plays important regulatory functions in diverse cells. However, there is still no visualization database for exploring global m6A patterns across cell lines. Here we collected all available MeRIP-Seq and m6A-CLIP-Seq datasets from public databases and identified 340,950 and 179,201 m6A peaks dependent on 23 human and eight mouse cell lines respectively. Those m6A peaks were further classified into mRNA and lncRNA groups. To better understand the potential function of m6A, we then mapped m6A peaks in different subcellular components and gene regions. Among those human m6A modification, 190,050 and 150,900 peaks were identified in cancer and non-cancer cells, respectively. Finally, all results were integrated and imported into a visualized cell-dependent m6A database CVm6A. We believe the specificity of CVm6A could significantly contribute to the research for the function and regulation of cell-dependent m6A modification in disease and development.


Assuntos
Adenosina/análogos & derivados , Bases de Dados como Assunto , Adenosina/metabolismo , Animais , Linhagem Celular , Humanos , Internet , Camundongos , Interface Usuário-Computador
10.
J Cell Biochem ; 120(4): 5936-5948, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30362152

RESUMO

Metastatic disease remains the primary cause of death for individuals with T cell acute lymphoblastic leukemia (T-ALL). microRNAs (miRNAs) play important roles in the pathogenesis of T-ALL by inhibiting gene expression at posttranscriptional levels. The goal of the current project is to identify any significant miRNAs in T-ALL metastasis. We observed miR-146b-5p to be downregulated in T-ALL patients and cell lines, and bioinformatics analysis implicated miR-146b-5p in the hematopoietic system. miR-146b-5p inhibited the migration and invasion in T-ALL cells. Interleukin-17A (IL-17A) was predicted to be a target of miR-146b-5p; this was confirmed by luciferase assays. Interestingly, T-ALL patients and cell lines secreted IL-17A and expressed the IL-17A receptor (IL-17RA). IL-17A/IL-17RA interactions promoted strong T-ALL cell migration and invasion responses. Gene set enrichment analysis (GSEA) and quantitative polymerase chain reaction (qPCR) analysis indicated that matrix metallopeptidase-9 (MMP9), was a potential downstream effector of IL-17A activation, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was also implicated in this process. Moreover, IL-17A activation promoted T-ALL cell metastasis to the liver in IL17A -/- mouse models. These results indicate that reduced miR-146b-5p expression in T-ALL may lead to the upregulation of IL-17A, which then promotes T-ALL cell migration and invasion by upregulating MMP9 via NF-κB signaling.


Assuntos
Interleucina-17/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Biologia Computacional , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-17/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs , Reação em Cadeia da Polimerase em Tempo Real , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Commun ; 9(1): 670, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29426862

RESUMO

The original version of this Article contained an error in the spelling of the author James C. Mulloy, which was incorrectly given as James Mulloy. This has now been corrected in both the PDF and HTML versions of the Article.

13.
Cancer Res ; 78(6): 1418-1430, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29339538

RESUMO

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-METSignificance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. Cancer Res; 78(6); 1418-30. ©2018 AACR.


Assuntos
Histona Desmetilases/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/virologia , Animais , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Interações Hospedeiro-Patógeno/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Camundongos Nus , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Repressoras/genética , Ubiquitinação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
14.
Toxicol Appl Pharmacol ; 341: 64-76, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29343424

RESUMO

Our previous study proposed a glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming mechanism for prenatal caffeine exposure (PCE)-induced adrenal developmental dysfunction. Here, we focused on PCE-induced cell proliferation changes of the adrenal cortex in male offspring rats before and after birth and clarified the intrauterine programming mechanism. On gestational day (GD) 20, the PCE group had an elevated serum corticosterone level reduced fetal bodyweight, maximum adrenal sectional area, and elevated adrenal corticosterone and aldosterone contents. However, in postnatal week (PW) 6, the serum corticosterone level was decreased, and the bodyweight, with catch-up growth, adrenal cortex maximum cross-sectional area and aldosterone content were relatively increased, while the adrenal corticosterone content was lower. On GD20, the expression of adrenal IGF1, IGF1R and proliferating cell nuclear antigen (PCNA) were decreased, while the expression of these factors at PW6 were increased in the PCE group. Fetal adrenal gene chip analysis suggested that the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) signal pathway was suppressed in the PCE group. Moreover, in the rat primary adrenal cells, corticosterone (rather than caffeine) was shown to significantly inhibit cell proliferation, IGF1 and PCNA expression, and ERK phosphorylation, which could be reversed by exogenous IGF1. Meanwhile, the effects of exogenous IGF1 were reversed by the ERK pathway inhibitor (PD184161). In conclusion, PCE could induce programming alterations in adrenal cortical cell proliferation before and after birth in male offspring rats. The underlying mechanism is associated with the inhibition of fetal adrenal IGF1-related MAPK/ERK signaling pathway caused by high glucocorticoid levels.


Assuntos
Córtex Suprarrenal/metabolismo , Cafeína/toxicidade , Proliferação de Células/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Córtex Suprarrenal/citologia , Córtex Suprarrenal/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Cafeína/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Distribuição Aleatória , Ratos , Ratos Wistar
15.
Brief Bioinform ; 19(4): 627-635, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28203711

RESUMO

Long noncoding RNAs (lncRNAs) are a large family of noncoding RNAs that play a critical role in various normal bioprocesses as well as tumorigenesis. However, the expression patterns and biological functions of lncRNAs in acute leukemia have not been well studied. Here, we performed transcriptome-wide lncRNA expression profiling of acute myeloid leukemia (AML) patient samples, along with non-leukemia control hematopoietic samples. We found that lncRNAs were differentially expressed in AML samples relative to control samples. Notably, we identified that lncRNAs upregulated in AML (relative to the control samples) are associated with a lower degree of DNA methylation and a higher ratio of being bound by transcription factors such as SP1, STAT4, ATF-2 and ELK-1 compared with those downregulated in AML. Moreover, an enrichment of H3K4me3 and a depletion of H3K27me3 were observed in upregulated lncRNAs in AML. Expression patterns of three types of lncRNAs (antisense, enhancer and intergenic lncRNAs) have previously been characterized. Of the identified lncRNAs, we found that high expression level lncRNA LOC285758 is associated with the poor prognosis in AML patients. Furthermore, we found that LOC285758 regulates proliferation of AML cell lines by enhancing the expression of HDAC2, a key factor in carcinogenesis. Collectively, our study depicts a landscape of important lncRNAs in AML and provides novel potential therapeutic targets and prognostic markers for AML treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/genética , Transcriptoma , Estudos de Casos e Controles , Histona Desacetilase 2/genética , Humanos , Células Tumorais Cultivadas
16.
Nucleic Acids Res ; 46(D1): D925-D929, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29036403

RESUMO

Circular RNA (circRNA) is a large group of RNA family extensively existed in cells and tissues. High-throughput sequencing provides a way to view circRNAs across different samples, especially in various diseases. However, there is still no comprehensive database for exploring the cancer-specific circRNAs. We collected 228 total RNA or polyA(-) RNA-seq samples from both cancer and normal cell lines, and identified 272 152 cancer-specific circRNAs. A total of 950 962 circRNAs were identified in normal samples only, and 170 909 circRNAs were identified in both tumor and normal samples, which could be further used as non-tumor background. We constructed a cancer-specific circRNA database (CSCD, http://gb.whu.edu.cn/CSCD). To understand the functional effects of circRNAs, we predicted the microRNA response element sites and RNA binding protein sites for each circRNA. We further predicted potential open reading frames to highlight translatable circRNAs. To understand the association between the linear splicing and the back-splicing, we also predicted the splicing events in linear transcripts of each circRNA. As the first comprehensive cancer-specific circRNA database, we believe CSCD could significantly contribute to the research for the function and regulation of cancer-associated circRNAs.


Assuntos
Neoplasias/genética , RNA Neoplásico/genética , RNA/genética , Sítios de Ligação , Biomarcadores Tumorais , Linhagem Celular , Linhagem Celular Tumoral , Coleta de Dados , Previsões , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fases de Leitura Aberta/genética , RNA/isolamento & purificação , Processamento de RNA , RNA Circular , RNA Neoplásico/isolamento & purificação , Proteínas de Ligação a RNA/metabolismo , Elementos de Resposta , Navegador
17.
Brief Bioinform ; 19(6): 1310-1316, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29106456

RESUMO

Circular RNAs (circRNAs) are novel rising stars of noncoding RNAs, which are highly abundant and evolutionarily conserved across species. Number of publications related to circRNAs increased sharply in recent years, representing emerging focuses in the field. Therefore, tools, pipelines and databases have been developed to identify and store circRNAs. However, there is no existing tool to visualize and explore circRNAs. Therefore, we introduce CircView, a user-friendly visualization tool for circRNAs detected from existing tools. CircView enables users to visualize circRNAs and to quantify number of samples with detected circRNAs. CircView allows users to explore circRNAs detected by unique or multiple tools. Furthermore, CircView allows users to view the regulatory elements, such as microRNA response elements and RNA-binding protein binding sites. CircView is a unique tool to visualize and explore circRNAs, which helps users to better understand potential functions of circRNAs and design the functional experiments.


Assuntos
RNA/química , Evolução Molecular , Conformação de Ácido Nucleico , RNA Circular , Especificidade da Espécie
18.
Nat Commun ; 8(1): 2099, 2017 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-29235481

RESUMO

Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.


Assuntos
Inibidores Enzimáticos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Oxigenases de Função Mista/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT5/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Daunorrubicina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos Endogâmicos C57BL , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Células THP-1
19.
Brief Bioinform ; 18(6): 984-992, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27543790

RESUMO

Circular RNA (circRNA) is a group of RNA family generated by RNA circularization, which was discovered ubiquitously across different species and tissues. However, there is no global view of tissue specificity for circRNAs to date. Here we performed the comprehensive analysis to characterize the features of human and mouse tissue-specific (TS) circRNAs. We identified in total 302 853 TS circRNAs in the human and mouse genome, and showed that the brain has the highest abundance of TS circRNAs. We further confirmed the existence of circRNAs by reverse transcription polymerase chain reaction (RT-PCR). We also characterized the genomic location and conservation of these TS circRNAs and showed that the majority of TS circRNAs are generated from exonic regions. To further understand the potential functions of TS circRNAs, we identified microRNAs and RNA binding protein, which might bind to TS circRNAs. This process suggested their involvement in development and organ differentiation. Finally, we constructed an integrated database TSCD (Tissue-Specific CircRNA Database: http://gb.whu.edu.cn/TSCD) to deposit the features of TS circRNAs. This study is the first comprehensive view of TS circRNAs in human and mouse, which shed light on circRNA functions in organ development and disorders.


Assuntos
Feto/metabolismo , Genoma , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , RNA/genética , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , RNA Circular
20.
J Am Coll Cardiol ; 68(19): 2086-2096, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27810048

RESUMO

BACKGROUND: Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder. OBJECTIVES: The objective of this study was to examine single cell mechanism of Brugada syndrome using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). METHODS: This study recruited 2 patients with type 1 BrS carrying 2 different sodium voltage-gated channel alpha subunit 5 variants as well as 2 healthy control subjects. We generated iPSCs from their skin fibroblasts by using integration-free Sendai virus. We used directed differentiation to create purified populations of iPSC-CMs. RESULTS: BrS iPSC-CMs showed reductions in inward sodium current density and reduced maximal upstroke velocity of action potential compared with healthy control iPSC-CMs. Furthermore, BrS iPSC-CMs demonstrated increased burden of triggered activity, abnormal calcium (Ca2+) transients, and beating interval variation. Correction of the causative variant by genome editing was performed, and resultant iPSC-CMs showed resolution of triggered activity and abnormal Ca2+ transients. Gene expression profiling of iPSC-CMs showed clustering of BrS compared with control subjects. Furthermore, BrS iPSC-CM gene expression correlated with gene expression from BrS human cardiac tissue gene expression. CONCLUSIONS: Patient-specific iPSC-CMs were able to recapitulate single-cell phenotype features of BrS, including blunted inward sodium current, increased triggered activity, and abnormal Ca2+ handling. This novel human cellular model creates future opportunities to further elucidate the cellular disease mechanism and identify novel therapeutic targets.


Assuntos
Síndrome de Brugada/genética , Regulação da Expressão Gênica , Sistema de Condução Cardíaco/fisiopatologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , RNA/genética , Adolescente , Adulto , Síndrome de Brugada/metabolismo , Síndrome de Brugada/patologia , Diferenciação Celular , Eletrocardiografia , Genótipo , Sistema de Condução Cardíaco/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/biossíntese , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Adulto Jovem
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