Department of Biohealth Informatics, School of Informatics and Computing, Indiana University Purdue University, 719 Indiana Ave Ste 319, Walker Plaza Building, Indianapolis, IN 46202, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 5021 Health Information and Translational Sciences (HITS), 410 West 10th Street, Indianapolis, IN 46202, USA.
Int J Mol Sci. 2020 Sep 25;21(19):7090. doi: 10.3390/ijms21197090.
The outbreak of a novel coronavirus SARS-CoV-2 responsible for the COVID-19 pandemic has caused a worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2-mediated alterations on post-transcriptional gene regulations across human tissues remain elusive. In this study, we analyzed publicly available genomic datasets to systematically dissect the crosstalk and dysregulation of the human post-transcriptional regulatory networks governed by RNA-binding proteins (RBPs) and micro-RNAs (miRs) due to SARS-CoV-2 infection. We uncovered that 13 out of 29 SARS-CoV-2-encoded proteins directly interacted with 51 human RBPs, of which the majority of them were abundantly expressed in gonadal tissues and immune cells. We further performed a functional analysis of differentially expressed genes in mock-treated versus SARS-CoV-2-infected lung cells that revealed enrichment for the immune response, cytokine-mediated signaling, and metabolism-associated genes. This study also characterized the alternative splicing events in SARS-CoV-2-infected cells compared to the control, demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to the viral infection. A motif enrichment analysis on the RNA genomic sequence of SARS-CoV-2 clearly revealed the enrichment for RBPs such as SRSFs, PCBPs, ELAVs, and HNRNPs, suggesting the sponging of RBPs by the SARS-CoV-2 genome. A similar analysis to study the interactions of miRs with SARS-CoV-2 revealed functionally important miRs that were highly expressed in immune cells, suggesting that these interactions may contribute to the progression of the viral infection and modulate the host immune response across other human tissues. Given the need to understand the interactions of SARS-CoV-2 with key post-transcriptional regulators in the human genome, this study provided a systematic computational analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs across tissue types during a SARS-CoV-2 infection.
新型冠状病毒 SARS-CoV-2 引发的 COVID-19 大流行已构成全球性公共卫生紧急事件。由于冠状病毒具有不断演变的特性，SARS-CoV-2 介导的人类组织中转录后基因调控的改变仍难以捉摸。在这项研究中，我们分析了公开的基因组数据集，以系统地剖析 SARS-CoV-2 感染后 RNA 结合蛋白 (RBPs) 和 microRNAs (miRs) 调控的人类转录后调控网络的串扰和失调。我们发现，29 种 SARS-CoV-2 编码蛋白中有 13 种可直接与 51 种人类 RBPs 相互作用，其中大多数在生殖组织和免疫细胞中大量表达。我们进一步对模拟处理与 SARS-CoV-2 感染的肺细胞中的差异表达基因进行了功能分析，结果表明，免疫反应、细胞因子介导的信号转导和代谢相关基因富集。本研究还对 SARS-CoV-2 感染细胞与对照细胞的选择性剪接事件进行了特征描述，表明跳过外显子和互斥外显子是导致病毒感染后差异结果的最丰富事件。对 SARS-CoV-2 基因组 RNA 序列的 motif 富集分析清楚地表明，SRSFs、PCBP、ELAV 和 HNRNPs 等 RBPs 存在富集，这表明 SARS-CoV-2 基因组对 RBPs 的海绵作用。对 miRs 与 SARS-CoV-2 相互作用的类似分析揭示了在免疫细胞中高表达的功能重要的 miRs，这表明这些相互作用可能有助于病毒感染的进展，并调节其他人类组织中的宿主免疫反应。鉴于需要了解 SARS-CoV-2 与人类基因组中关键转录后调控因子的相互作用，本研究提供了一种系统的计算分析方法，以剖析 SARS-CoV-2 感染期间 RBPs 和 miRs 调控的失调转录后调控网络在不同组织类型中的作用。
