Tongji University, China.
Ewha Womans University, Korea.
Brief Bioinform. 2021 Sep 2;22(5). doi: 10.1093/bib/bbaa438.
Exon skipping (ES), the most common alternative splicing event, has been reported to contribute to diverse human diseases due to the loss of functional domains/sites or frameshifting of the open reading frame (ORF) and noticed as therapeutic targets. Accumulating transcriptomic studies of aging brains show the splicing disruption is a widespread hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Here, we built ExonSkipAD, the ES annotation database aiming to provide a resource/reference for functional annotation of ES events in AD and identify therapeutic targets in exon units. We identified 16 414 genes that have ~156 K, ~ 69 K, ~ 231 K ES events from the three representative AD cohorts of ROSMAP, MSBB and Mayo, respectively. For these ES events, we performed multiple functional annotations relating to ES mechanisms or downstream. Specifically, through the functional feature retention studies followed by the open reading frames (ORFs), we identified 275 important cellular regulators that might lose their cellular regulator roles due to exon skipping in AD. ExonSkipAD provides twelve categories of annotations: gene summary, gene structures and expression levels, exon skipping events with PSIs, ORF annotation, exon skipping events in the canonical protein sequence, 3'-UTR located exon skipping events lost miRNA-binding sites, SNversus in the skipped exons with a depth of coverage, AD stage-associated exon skipping events, splicing quantitative trait loci (sQTLs) in the skipped exons, correlation with RNA-binding proteins, and related drugs & diseases. ExonSkipAD will be a unique resource of transcriptomic diversity research for understanding the mechanisms of neurodegenerative disease development and identifying potential therapeutic targets in AD. Significance AS the first comprehensive resource of the functional genomics of the alternative splicing events in AD, ExonSkipAD will be useful for many researchers in the fields of pathology, AD genomics and precision medicine, and pharmaceutical and therapeutic researches.
外显子跳跃 (ES) 是最常见的可变剪接事件，由于功能域/位点的缺失或开放阅读框 (ORF) 的移码，导致多种人类疾病，并被认为是治疗靶点。对衰老大脑的转录组学研究表明，剪接紊乱是阿尔茨海默病 (AD) 等神经退行性疾病的广泛标志。在这里，我们构建了 ExonSkipAD，这是一个 ES 注释数据库，旨在为 AD 中外显子跳跃事件的功能注释提供资源/参考，并确定外显子单位的治疗靶点。我们从 ROSMAP、MSBB 和 Mayo 的三个代表性 AD 队列中分别鉴定出 16414 个基因，这些基因有约 156K、69K、231K 的 ES 事件。对于这些 ES 事件，我们进行了与 ES 机制或下游相关的多种功能注释。具体来说，通过功能特征保留研究和随后的开放阅读框 (ORFs)，我们确定了 275 个重要的细胞调节剂，由于 AD 中外显子跳跃，它们可能失去细胞调节剂的作用。ExonSkipAD 提供了十二类注释：基因摘要、基因结构和表达水平、PSI 下的外显子跳跃事件、ORF 注释、规范蛋白序列中外显子跳跃事件、3'-UTR 中外显子跳跃事件丧失 miRNA 结合位点、SN 在跳过外显子中的覆盖率、与 AD 阶段相关的外显子跳跃事件、在跳过外显子中的剪接数量性状基因座 (sQTLs)、与 RNA 结合蛋白的相关性，以及相关药物和疾病。ExonSkipAD 将成为理解神经退行性疾病发展机制和确定 AD 中潜在治疗靶点的转录组多样性研究的独特资源。意义作为 AD 中外显子跳跃事件功能基因组学的第一个全面资源，ExonSkipAD 将对病理、AD 基因组学和精准医学以及制药和治疗研究领域的许多研究人员有用。
