Investigação sobre o papel dos RNAs longos não codificantes no contexto do sarcoma de Ewing
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Data
2022-02-10
Autores
Coan, Rafael Luiz Buogo
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Universidade Estadual Paulista (Unesp)
Resumo
O sarcoma de Ewing (SE) é um câncer que tipicamente afeta ossos e tecidos moles, especialmente em crianças e adultos jovens. As células neoplásicas do SE apresentam uma translocação recorrente entre os genes EWSR1 e FLI1, localizados respectivamente nos cromossomos 11 e 22. Esta translocação resulta na proteína fusionada EWS-FLI1, que age como um fator de transcrição aberrante desregulando a expressão de ampla gama de genes. Por exemplo, via ligação em repetições GGAA presentes de genes codificadores de proteínas, EWS-FLI1 recruta histonas deacetilases (HDACs), enzimas que modulam epigeneticamente a transcrição de genes codificadores e não codificadores, como os RNAs longos não codificantes (lncRNA). Estes atuam sob diversas formas, por exemplo, inibindo complexos enzimáticos, interferindo diretamente no DNA ou com outras moléculas de RNA. Como característica em comum, lncRNAs e HDACs participam em complexos remodeladores de cromatina (e.g. NuRD), assim regulando a expressão gênica globalmente. Estudos experimentais e clínicos recentemente reportaram que inibidores de HDACs (HDACi) têm promissor potencial antineoplásico contra células de SE. No entanto, pouco é conhecido sobre a associação entre os moduladores epigenéticos e os lncRNA no contexto do SE. Este estudo emprega a biologia de sistemas para investigar as relações entre as principais formas da translocação EWS-FLI1 encontradas no SE e moléculas envolvidas em mecanismos conhecidos de modulação epigenética da expressão gênica, como no remodelamento de cromatina (HDACs) e regulação pós-transcricional (lncRNA). Objetivamos, além, estabelecer um pipeline computacional para identificar novos transcritos não codificantes no SE. Por meio de dados de RNA-Seq provenientes de tumores sequenciados de SE, depositados no dbGaP, calculamos a expressão gênica de codificadores e não codificadores de proteína. Após, construímos uma rede de coexpressão que revela as associações entre lncRNA conhecidos e HDACs. O enriquecimento de vias e o uso de banco de dados auxilia-nos na interpretação dos resultados nas diferentes etapas do estudo. Ademais, encontramos lncRNA candidatos a novos transcritos no contexto do SE. Por fim, nosso estudo estabelece conexões entre HDACs e lncRNA, além de encontrar novos transcritos associados ao SE.
Ewing sarcoma (ES) is a cancer that usually affects bones and soft tissues, especially in children and young adults. Neoplastic SE cells have a recurrent translocation between EWSR1 and FLI1, genes that are located on chromosomes 11 and 22, respectively. Such translocation results in the fusion protein EWS-FLI1, which acts as an aberrant transcriptional factor deregulating genome-wide gene expression. For example, through binding with GGAA repetitions present in protein-coding genes, EWS-FLI1 recruits histone deacetylases (HDAC), enzymes that epigenetically modulate gene expression of both protein-coding and non-coding genes, such as long non-coding RNAs (lncRNA). These act in many ways, for example, by inhibiting enzymatic complexes, directly interfering with DNA or other RNA molecules. As a common characteristic, lncRNAs and HDACs participate in chromatin remodeling complexes (e.g., NuRD), thus regulating gene-wide expression. Experimental and clinical studies report that HDACs inhibitors (HDACi) have promising potential as antineoplastic drugs against ES cells. However, little is known about the relationship between epigenetic modulators and lncRNA in the context of ES. This study employs systems biology to investigate the association between the main forms of EWS-FLI1 translocation and the molecules involved in known epigenetic modulation of gene expression, such as chromatin remodeling (HDACs) and post transcriptional regulation (lncRNA). Besides, our objective is to establish a computational pipeline to identify new non-coding transcripts on ES. With RNA-Seq data from sequenced patient tumors of dbGaP, we calculated the expression of coding and non-coding genes. We constructed a coexpression network that shows the associations between known lncRNA and HDACs. Pathway and gene ontology enrichment analysis, together with external databases, helped us interpret the results. In addition, we found new candidates for lncRNA on ES. Therefore, our study establishes connections between HDACs and lncRNA, besides finding new transcripts associated with ES.
Ewing sarcoma (ES) is a cancer that usually affects bones and soft tissues, especially in children and young adults. Neoplastic SE cells have a recurrent translocation between EWSR1 and FLI1, genes that are located on chromosomes 11 and 22, respectively. Such translocation results in the fusion protein EWS-FLI1, which acts as an aberrant transcriptional factor deregulating genome-wide gene expression. For example, through binding with GGAA repetitions present in protein-coding genes, EWS-FLI1 recruits histone deacetylases (HDAC), enzymes that epigenetically modulate gene expression of both protein-coding and non-coding genes, such as long non-coding RNAs (lncRNA). These act in many ways, for example, by inhibiting enzymatic complexes, directly interfering with DNA or other RNA molecules. As a common characteristic, lncRNAs and HDACs participate in chromatin remodeling complexes (e.g., NuRD), thus regulating gene-wide expression. Experimental and clinical studies report that HDACs inhibitors (HDACi) have promising potential as antineoplastic drugs against ES cells. However, little is known about the relationship between epigenetic modulators and lncRNA in the context of ES. This study employs systems biology to investigate the association between the main forms of EWS-FLI1 translocation and the molecules involved in known epigenetic modulation of gene expression, such as chromatin remodeling (HDACs) and post transcriptional regulation (lncRNA). Besides, our objective is to establish a computational pipeline to identify new non-coding transcripts on ES. With RNA-Seq data from sequenced patient tumors of dbGaP, we calculated the expression of coding and non-coding genes. We constructed a coexpression network that shows the associations between known lncRNA and HDACs. Pathway and gene ontology enrichment analysis, together with external databases, helped us interpret the results. In addition, we found new candidates for lncRNA on ES. Therefore, our study establishes connections between HDACs and lncRNA, besides finding new transcripts associated with ES.
Descrição
Palavras-chave
Sarcoma de Ewing, lncRNA, HDAC, RNA-Seq