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1.
Virol J ; 16(1): 29, 2019 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-30832682

RESUMEN

BACKGROUND: Alternative splicing (AS) is an important mRNA maturation step that allows increased variability and diversity of proteins in eukaryotes. AS is dysregulated in numerous diseases, and its implication in the carcinogenic process is well known. However, progress in understanding how oncogenic viruses modulate splicing, and how this modulation is involved in viral oncogenicity has been limited. Epstein-Barr virus (EBV) is involved in various cancers, and its EBNA1 oncoprotein is the only viral protein expressed in all EBV malignancies. METHODS: In the present study, the ability of EBNA1 to modulate the AS of cellular genes was assessed using a high-throughput RT-PCR approach to examine AS in 1238 cancer-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by EBNA1. RESULTS: Upon EBNA1 expression, we detected modifications to the AS profiles of 89 genes involved in cancer. Moreover, we show that EBNA1 modulates the expression levels of various splicing factors such as hnRNPA1, FOX-2, and SF1. Finally, RNA immunoprecipitation coupled to RIP-Seq assays demonstrate that EBNA1 immunoprecipitates specific cellular mRNAs, but not the ones that are spliced differently in EBNA1-expressing cells. CONCLUSION: The EBNA1 protein can modulate the AS profiles of numerous cellular genes. Interestingly, this modulation protein does not require the RNA binding activity of EBNA1. Overall, these findings underline the novel role of EBNA1 as a cellular splicing modulator.


Asunto(s)
Empalme Alternativo , Antígenos Nucleares del Virus de Epstein-Barr/genética , Genes Relacionados con las Neoplasias , Herpesvirus Humano 4/genética , Interacciones Microbiota-Huesped/genética , Línea Celular Tumoral , Perfilación de la Expresión Génica , Genes Virales , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Virales/genética
2.
PLoS One ; 12(5): e0176880, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28493890

RESUMEN

Multiple human diseases including cancer have been associated with a dysregulation in RNA splicing patterns. In the current study, modifications to the global RNA splicing landscape of cellular genes were investigated in the context of Epstein-Barr virus-associated gastric cancer. Global alterations to the RNA splicing landscape of cellular genes was examined in a large-scale screen from 295 primary gastric adenocarcinomas using high-throughput RNA sequencing data. RT-PCR analysis, mass spectrometry, and co-immunoprecipitation studies were also used to experimentally validate and investigate the differential alternative splicing (AS) events that were observed through RNA-seq studies. Our study identifies alterations in the AS patterns of approximately 900 genes such as tumor suppressor genes, transcription factors, splicing factors, and kinases. These findings allowed the identification of unique gene signatures for which AS is misregulated in both Epstein-Barr virus-associated gastric cancer and EBV-negative gastric cancer. Moreover, we show that the expression of Epstein-Barr nuclear antigen 1 (EBNA1) leads to modifications in the AS profile of cellular genes and that the EBNA1 protein interacts with cellular splicing factors. These findings provide insights into the molecular differences between various types of gastric cancer and suggest a role for the EBNA1 protein in the dysregulation of cellular AS.


Asunto(s)
Empalme Alternativo/genética , Infecciones por Virus de Epstein-Barr/genética , Perfilación de la Expresión Génica , Herpesvirus Humano 4/fisiología , ARN Neoplásico/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/virología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/virología , Antígenos Nucleares del Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Unión Proteica , Factores de Empalme de ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Reproducibilidad de los Resultados , Neoplasias Gástricas/patología , Análisis de Supervivencia
3.
PLoS One ; 11(9): e0161914, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27598998

RESUMEN

Alternative splicing (AS) is a central mechanism of genetic regulation which modifies the sequence of RNA transcripts in higher eukaryotes. AS has been shown to increase both the variability and diversity of the cellular proteome by changing the composition of resulting proteins through differential choice of exons to be included in mature mRNAs. In the present study, alterations to the global RNA splicing landscape of cellular genes upon viral infection were investigated using mammalian reovirus as a model. Our study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in eukaryotic cells following infection with a human virus. We identify 240 modified alternative splicing events upon infection which belong to transcripts frequently involved in the regulation of gene expression and RNA metabolism. Using mass spectrometry, we also confirm modifications to transcript-specific peptides resulting from AS in virus-infected cells. These findings provide additional insights into the complexity of virus-host interactions as these splice variants expand proteome diversity and function during viral infection.


Asunto(s)
Empalme Alternativo , Fibroblastos/metabolismo , Genoma , Interacciones Huésped-Patógeno/genética , Orthoreovirus Mamífero 3/crecimiento & desarrollo , ARN Mensajero/genética , Secuencia de Aminoácidos , Animales , Exones , Fibroblastos/virología , Ontología de Genes , Humanos , Orthoreovirus Mamífero 3/patogenicidad , Ratones , Anotación de Secuencia Molecular , Proteómica , ARN Mensajero/metabolismo , Análisis de Secuencia de ARN
4.
BMC Genomics ; 17: 683, 2016 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-27565572

RESUMEN

BACKGROUND: Dysregulations in alternative splicing (AS) patterns have been associated with many human diseases including cancer. In the present study, alterations to the global RNA splicing landscape of cellular genes were investigated in a large-scale screen from 377 liver tissue samples using high-throughput RNA sequencing data. RESULTS: Our study identifies modifications in the AS patterns of transcripts encoded by more than 2500 genes such as tumor suppressor genes, transcription factors, and kinases. These findings provide insights into the molecular differences between various types of hepatocellular carcinoma (HCC). Our analysis allowed the identification of 761 unique transcripts for which AS is misregulated in HBV-associated HCC, while 68 are unique to HCV-associated HCC, 54 to HBV&HCV-associated HCC, and 299 to virus-free HCC. Moreover, we demonstrate that the expression pattern of the RNA splicing factor hnRNPC in HCC tissues significantly correlates with patient survival. We also show that the expression of the HBx protein from HBV leads to modifications in the AS profiles of cellular genes. Finally, using RNA interference and a reverse transcription-PCR screening platform, we examined the implications of cellular proteins involved in the splicing of transcripts involved in apoptosis and demonstrate the potential contribution of these proteins in AS control. CONCLUSIONS: This study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in hepatocellular carcinoma. Moreover, these data allowed us to identify unique signatures of genes for which AS is misregulated in the different types of HCC.


Asunto(s)
Empalme Alternativo , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/virología , Análisis por Conglomerados , Perfilación de la Expresión Génica , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/virología , Factores de Empalme de ARN/genética , ARN Mensajero , Reproducibilidad de los Resultados , Transactivadores/genética , Transactivadores/metabolismo , Transcriptoma , Proteínas Reguladoras y Accesorias Virales
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