Targeting RNA Splicing in Glioma

胶质瘤中靶向RNA剪接的研究 RNA选择性剪接(AS)是一种进化上保守的共转录过程，调节 真核生物以及癌症等人类疾病中的转录组和蛋白质组景观。不像 已经进行了大量研究来描述胶质瘤基因组、转录本、 甲基组和蛋白质组，几乎没有做过将胶质瘤驱动基因突变与AS程序联系起来的工作 并评价AS表达异常对肿瘤恶性程度的影响。三例脑胶质瘤AS的临床分析 患者RNA-seq数据集表明，有两种胶质瘤亚型与世卫组织肿瘤分级有关， 胶质瘤基因突变与患者预后的关系。利用人类诱导的多能干细胞(HiPSC)- 衍生的胶质瘤阿凡达模型和临床胶质瘤模型，我们发现IDH1R132H/WT或PTEN-/- /CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII基因型别影响AS亚型。两个子集 影响RNA剪接的限制性商业惯例与这两种胶质瘤亚型有不同的相关性。 亚型相关RBPs或AS异构体的表达也会影响脑胶质瘤的事件和生长 类干细胞(GSCs)。在这个研究项目中，我们计划利用我们以前的贡献，现有的 研究计划、最新发现、新建立的胶质瘤头像模型、尖端CRISPR编辑 技术和卓越的科学前提来研究胶质瘤突变是否会影响程序 以及RNA结合蛋白(RBPs)和AS基因亚型如何对胶质瘤肿瘤生物学做出贡献。AS 还将利用各种计划进行治疗干预，以治疗胶质瘤。该项目将解决 我们对胶质瘤驱动基因突变和肿瘤相关关系的理解上的主要差距 作为计划，并测试靶向RNA剪接是否构成治疗的脆弱性 神经胶质瘤。在解决这些知识差距的过程中，这项研究将影响我们的理解和处理 胶质瘤的研究，这样做可能会影响其他癌症的研究。

Targeting RNA Splicing in Glioma RNA alternative splicing (AS) is an evolutionally conserved co-transcriptional process, regulates transcriptome and proteome landscapes in eukaryotes, and in human diseases such as cancer. Unlike the numerous studies that have been conducted for characterizing glioma genomes, transcriptomes, methylomes, and proteomes, little has been done to associate glioma driver mutations with AS programs and evaluate the impact of dysregulated AS on cancer malignancy. Our analyses of AS in three glioma patient RNA-seq datasets indicate two AS glioma subtypes that show associations with WHO tumor grade, glioma driver mutations, and patient prognosis. Utilizing a human induced pluripotent stem cell (hiPSC)- derived glioma “avatar” model and clinical glioma models, we show that IDH1R132H/WT or PTEN-/- /CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII genotypes influence subtype-associated AS programs. Two subsets of RBPs that affect RNA splicing are differentially associated with these two AS glioma subtypes. Expression of subtype-associated RBPs or AS isoforms also affected AS events and growth of glioma stem-like cells (GSCs). In this research project, we plan to leverage our previous contributions, existing research program, recent findings, newly established glioma avatar models, cutting-edge CRISPR editing technology, and outstanding scientific premise to study whether glioma mutations influence AS programs and how RNA binding proteins (RBPs) and AS gene isoforms contribute to glioma tumor biology. AS programs will also be exploited for therapeutic intervention in treating gliomas. This project will address key gaps in our understanding of the relationships between glioma driver mutations and tumor-associated AS programs, and test whether targeting RNA splicing constitutes a therapeutic vulnerability to treat gliomas. In addressing these knowledge gaps this research will influence our understanding and treatment of glioma, and in so doing will likely influence the study of other cancers.