Methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 RNA N6-methyladenosine modification and replication

Zhang, Xueyan; Hao, Haojie; Ma, Li; Zhang, Yecheng; Hu, Xiao; Chen, Zhe; Liu, Di; Yuan, Jun; Hu, Zhangli; Guan, Wuxiang

doi:10.1101/2020.10.14.338558

Cited by 16 publications

(40 citation statements)

References 62 publications

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“…Recently, the m6A methylation machinery was identified to play a key role in the context of SARS-CoV-2, with studies reporting widespread alterations of the viral and host RNA m6A methylome following infection [Xu et al (2021)]. Further, altered expression levels of methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) linked to viral replication [Zhang et al (2020)]. FTO is a demethylase (eraser) enzyme with enriched binding in the 3’ UTR of mRNAs in mammals [Meyer et al (2012)].…”

Section: Resultsmentioning

confidence: 99%

“…Altered expression levels of methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) have been recently linked to viral replication (99). FTO is a demethylase (eraser) enzyme with enriched binding in the 3’ UTR of mRNAs in mammals (58).…”

Section: Resultsmentioning

confidence: 99%

“…FTO is a demethylase (eraser) enzyme with enriched binding in the 3’ UTR of mRNAs in mammals (58). FTO has previously been suggested as a potential drug target against COVID-19 (97), as targeted knockdown has been shown to significantly decrease SARS-CoV-2 infection (99; 97; 6). Therefore, we investigated predicted binding of FTO to the 3’ UTR of SARS-CoV-2 and related viruses.…”

Section: Resultsmentioning

confidence: 99%

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Computational Mapping of the Human-SARS-CoV-2 Protein-RNA Interactome

Horlacher

Oleshko

et al. 2021

Preprint

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It is well known that viruses make extensive use of the host cell's machinery, hijacking it for the purpose of viral replication and interfere with the activity of master regulatory proteins - including RNA binding proteins (RBPs). RBPs recognize and bind RNA molecules to control several steps of cellular RNA metabolism, such as splicing, transcript stability, translation and others, and recognize their targets by means of sequence or structure motifs. Host RBPs are critical factors for viral replication, especially for RNA viruses, and have been shown to influence viral RNA stability, replication and escape of host immune response. While current research efforts have been centered around identifying mechanisms of host cell-entry, the role of host RBPs in the context of SARS-CoV-2 replication remains poorly understood. Few experimental studies have started mapping the SARS-CoV-2 RNA-protein interactome in infected human cells, but they are limited in the resolution and exhaustivity of their output. On the other hand, computational approaches enable screening of large numbers of human RBPs for putative interactions with the viral RNA, and are thus crucial to prioritize candidates for further experimental investigation. Here, we investigate the role of RBPs in the context of SARS-CoV-2 by constructing a first single-nucleotide \textit{in silico} map of human RBP / viral RNA interactions by using deep learning models trained on RNA sequences. Our framework is based on Pysster and DeepRiPe, two deep learning method which use a convolutional neural network to learn sequence-structure preferences of a specific RBP. Models were trained using eCLIP and PAR-CLIP datasets for >150 RBP generated on human cell lines and applied cross-species to predict the propensity of each RBP to bind the SARS-CoV-2 genome. After extensive validation of predicted binding sites, we generate RBP binding profiles across different SARS-CoV-2 variants and 6 other betacoronaviruses. We address the questions of (1) conservation of binding between pathogenic betacoronaviruses, (2) differential binding across viral strains and (3) gain and loss of binding events in novel mutants which can be linked to disease severity and spread in the population. In addition, we explore the specific pathways hijacked by the virus, by integrating host factors linked to these virus-binding RBPs through protein-protein interaction networks or genome wide CRISPR screening. We believe that identifying viral RBP binding sites will give valuable insights into the mechanisms of host-virus interaction, thus giving us a deeper understanding of the life cycle of SARS-CoV-2 but also opening new avenues for the development of new therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Computational Mapping of the Human-SARS-CoV-2 Protein-RNA Interactome

Horlacher

Oleshko

et al. 2021

Preprint

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“…A detailed investigation is essential to understand whether SARS-CoV-2 RNA is subjected to m6A modifications and its role in virus replication and viral particle synthesis in the host cells. Moreover, a recent report has shown that SARS-CoV-2 protein interacts with host m6A machinery for efficient infection ( Zhang et al, 2020 ).…”

Section: Host Epigenetic Players In Generation Of Sars-cov-2 Virusmentioning

confidence: 99%

The severity of SARS-CoV-2 infection is dictated by host factors? Epigenetic perspectives

Sethumadhavan

Jabeena

Govindaraju

et al. 2021

Current Research in Microbial Sciences

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“…Especially, which can affect the replication of the virus and the host's innate immunity. A recent study has found that the host m6A modification complex interacted with SARS-CoV-2 proteins to modulate SARS-CoV-2 replication [13]. m 6 A epitranscriptome of Kaposi sarcomaassociated herpesvirus (KSHV) was recently mapped.…”

mentioning

confidence: 99%