Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Molecular, Cellular and Integrative Physiology Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Genome Biol. 2020 Oct 26;21(1):268. doi: 10.1186/s13059-020-02171-4.
RNA editing generates modifications to the RNA sequences, thereby increasing protein diversity and shaping various layers of gene regulation. Recent studies have revealed global shifts in editing levels across many cancer types, as well as a few specific mechanisms implicating individual sites in tumorigenesis or metastasis. However, most tumor-associated sites, predominantly in noncoding regions, have unknown functional relevance.
Here, we carry out integrative analysis of RNA editing profiles between epithelial and mesenchymal tumors, since epithelial-mesenchymal transition is a key paradigm for metastasis. We identify distinct editing patterns between epithelial and mesenchymal tumors in seven cancer types using TCGA data, an observation further supported by single-cell RNA sequencing data and ADAR perturbation experiments in cell culture. Through computational analyses and experimental validations, we show that differential editing sites between epithelial and mesenchymal phenotypes function by regulating mRNA abundance of their respective genes. Our analysis of RNA-binding proteins reveals ILF3 as a potential regulator of this process, supported by experimental validations. Consistent with the known roles of ILF3 in immune response, epithelial-mesenchymal differential editing sites are enriched in genes involved in immune and viral processes. The strongest target of editing-dependent ILF3 regulation is the transcript encoding PKR, a crucial player in immune and viral response.
Our study reports widespread differences in RNA editing between epithelial and mesenchymal tumors and a novel mechanism of editing-dependent regulation of mRNA abundance. It reveals the broad impact of RNA editing in cancer and its relevance to cancer-related immune pathways.
RNA 编辑会对 RNA 序列进行修饰，从而增加蛋白质的多样性，并塑造各种基因调控层次。最近的研究揭示了许多癌症类型中编辑水平的全局变化，以及一些涉及个别位点在肿瘤发生或转移中的特定机制。然而，大多数与肿瘤相关的位点主要位于非编码区域，其功能相关性尚不清楚。
在这里，我们对上皮和间充质肿瘤的 RNA 编辑谱进行了综合分析，因为上皮-间充质转化是转移的关键范例。我们使用 TCGA 数据在七种癌症类型中识别出上皮和间充质肿瘤之间的不同编辑模式，这一观察结果进一步得到单细胞 RNA 测序数据和细胞培养中 ADAR 扰动实验的支持。通过计算分析和实验验证，我们表明上皮和间充质表型之间的差异编辑位点通过调节各自基因的 mRNA 丰度起作用。我们对 RNA 结合蛋白的分析表明，ILF3 可能是这个过程的调节剂，实验验证也支持了这一观点。与 ILF3 在免疫反应中的已知作用一致，上皮-间充质差异编辑位点富集在参与免疫和病毒过程的基因中。编辑依赖性 ILF3 调节的最强靶标是编码 PKR 的转录本，PKR 是免疫和病毒反应中的关键参与者。
我们的研究报告了上皮和间充质肿瘤之间广泛存在的 RNA 编辑差异，以及一种新的基于编辑的 mRNA 丰度调节机制。它揭示了 RNA 编辑在癌症中的广泛影响及其与癌症相关免疫途径的相关性。
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