Abstract：
Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3\' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3\' UTRs remains largely unknown. Here, we find that 3\' UTR IRAlus silences genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3\' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3\' UTR IRAlus and its role in human pathophysiology.
摘要：
反向Alu重复序列（IRAlus）在转录组中大量存在，特别是在内含子和3'非翻译区（UTR）。然而，在3个UTR中嵌入IRAlus的生物学意义仍然未知。这里,我们发现3'UTRIRAlus沉默参与必需信号通路的基因。我们利用J2抗体直接捕获和定位转录组中3'UTRIRAlus的双链RNA结构。生物信息学分析揭示了替代性聚腺苷酸化是IRAlus介导的基因调控的主轴。值得注意的是,小鼠双分2（MDM2）的表达，p53的抑制剂，在UTR缩短期间通过排除IRAlus上调，它被用来在肿瘤发生过程中沉默p53。此外，神经祖细胞中的全转录组UTR延长导致与神经退行性疾病相关的基因的全球下调，包括肌萎缩侧索硬化症,通过包含IRAlus。我们的研究建立了3'UTRIRAlus的功能景观及其在人类病理生理学中的作用。
