Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma.
Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma.
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DOI：
10.1186/s13059-016-0990-4
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发表时间：
2016-06-10
期刊：
影响因子：
12.3
通讯作者：
Penalva LO
中科院分区：
文献类型：
--
作者：
Correa BR;de Araujo PR;Qiao M;Burns SC;Chen C;Schlegel R;Agarwal S;Galante PA;Penalva LO
胶质母细胞瘤（GBM）是最常见和最具侵袭性的脑肿瘤类型。目前，GBM的预后极差，没有有效的治疗方法。在这种情况下，基因组和转录组学分析已成为确定新的治疗途径的重要工具。RNA结合蛋白（RBP）是共转录和转录后事件的主要调节因子，然而，它们在GBM中的作用仍然知之甚少。为了进一步了解可能有助于胶质瘤形成的新的调控途径，我们对GBM中的RBP进行了系统的研究。通过测量GBM样品和神经胶质瘤干细胞样品中1542种人RBPs的表达水平，我们鉴定了58种一致上调的RBPs。生存分析显示，21个RBP的表达增加也与预后不良相关。为了评估这些RBP的功能影响，我们调节它们在GBM细胞系中的表达，并进行活力、增殖和凋亡测定。综合结果揭示了一个突出的致癌候选人，SNRPB，编码核心剪接体机械组件。为了揭示SNRPB对剪接和基因表达的影响，我们在GBM细胞系中进行了其敲除，然后进行RNA测序。我们发现受影响的基因参与RNA加工，DNA修复和染色质重塑。此外，已经与胶质瘤发生相关的基因和途径，以及一组一般的癌症基因，也出现了剪接和表达改变。我们的研究为RBP，特别是SNRPB如何调节基因表达并直接影响GBM发育提供了新的见解。本文的在线版本（doi：10.1186/s13059-016-0990-4）包含补充材料，可供授权用户使用。
Glioblastoma (GBM) is the most common and aggressive type of brain tumor. Currently, GBM has an extremely poor outcome and there is no effective treatment. In this context, genomic and transcriptomic analyses have become important tools to identify new avenues for therapies. RNA-binding proteins (RBPs) are master regulators of co- and post-transcriptional events; however, their role in GBM remains poorly understood. To further our knowledge of novel regulatory pathways that could contribute to gliomagenesis, we have conducted a systematic study of RBPs in GBM. By measuring expression levels of 1542 human RBPs in GBM samples and glioma stem cell samples, we identified 58 consistently upregulated RBPs. Survival analysis revealed that increased expression of 21 RBPs was also associated with a poor prognosis. To assess the functional impact of those RBPs, we modulated their expression in GBM cell lines and performed viability, proliferation, and apoptosis assays. Combined results revealed a prominent oncogenic candidate, SNRPB, which encodes core spliceosome machinery components. To reveal the impact of SNRPB on splicing and gene expression, we performed its knockdown in a GBM cell line followed by RNA sequencing. We found that the affected genes were involved in RNA processing, DNA repair, and chromatin remodeling. Additionally, genes and pathways already associated with gliomagenesis, as well as a set of general cancer genes, also presented with splicing and expression alterations. Our study provides new insights into how RBPs, and specifically SNRPB, regulate gene expression and directly impact GBM development. The online version of this article (doi:10.1186/s13059-016-0990-4) contains supplementary material, which is available to authorized users.