Srivastava Rajneesh, Daulatabad Swapna Vidhur, Srivastava Mansi, Janga Sarath Chandra
Department of Biohealth Informatics, School of Informatics and Computing, Indiana University Purdue University, 719 Indiana Ave Ste 319, Walker Plaza Building, Indianapolis, Indiana 46202.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 5021 Health Information and Translational Sciences (HITS), 410 West 10th Street, Indianapolis, Indiana, 46202.
bioRxiv. 2020 Sep 22:2020.07.06.190348. doi: 10.1101/2020.07.06.190348.
The outbreak of a novel coronavirus SARS-CoV-2 responsible for COVID-19 pandemic has caused worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2 mediated alteration on post-transcriptional gene regulation across human tissues remains elusive. In this study, we analyze publicly available genomic datasets to systematically dissect the crosstalk and dysregulation of 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 interact with 51 human RBPs of which 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 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 control demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to viral infection. 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 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 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 provides a systematic computational analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs, across tissues types during SARS-CoV-2 infection.
导致COVID-19大流行的新型冠状病毒SARS-CoV-2的爆发已引发全球公共卫生紧急事件。由于冠状病毒不断演变的特性，SARS-CoV-2介导的人类组织转录后基因调控变化仍不清楚。在本研究中，我们分析公开可用的基因组数据集，以系统剖析因SARS-CoV-2感染而由RNA结合蛋白（RBPs）和微小RNA（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种直接与51种人类RBPs相互作用，其中大多数在性腺组织和免疫细胞中大量表达。我们进一步对模拟处理的和SARS-CoV-2感染的肺细胞中差异表达基因进行功能分析，结果显示免疫反应、细胞因子介导的信号传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中的可变剪接事件进行了表征，表明外显子跳跃和互斥外显子是最丰富的事件，可能导致对病毒感染的不同反应结果。对SARS-CoV-2 RNA基因组序列的基序富集分析清楚地显示了SRSFs、PCBPs、ELAVs和HNRNPs等RBPs的富集，表明SARS-CoV-2基因组对RBPs的吸附作用。一项研究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，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节因子的相互作用，本研究提供了一项系统的计算分析，以剖析在SARS-CoV-2感染期间跨组织类型由RBPs和miRs控制的失调转录后调控网络的作用。
