Environmentally-induced mdig is a major contributor to the severity of COVID-19 through fostering expression of SARS-CoV-2 receptor NRPs and glycan metabolism

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Abstract

The novel β-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has infected more than 101 million people and resulted in 2.2 million death worldwide. Recent epidemiological studies suggested that some environmental factors, such as air pollution, might be the important contributors to the mortality of COVID-19. However, how environmental exposure enhances the severity of COVID-19 remains to be fully understood. In the present report, we provide evidence showing that mdig, a previously reported environmentally-induced oncogene that antagonizes repressive trimethylation of histone proteins, is a master regulator for SARS-CoV-2 receptors neuropilin-1 (NRP1) and NRP2, cathepsins, glycan metabolism and inflammation, key determinants for viral infection and cytokine storm of the patients. Depletion of mdig in bronchial epithelial cells by CRISPR-Cas-9 gene editing resulted in a decreased expression of NRP1, NRP2, cathepsins, and genes involved in protein glycosylation and inflammation, largely due to a substantial enrichment of lysine 9 and/or lysine 27 trimethylation of histone H3 (H3K9me3/H3K27me3) on these genes as determined by ChIP-seq. These data, accordingly, suggest that mdig is a key mediator for the severity of COVID-19 in response to environmental exposure and targeting mdig may be one of the effective strategies in ameliorating the symptom and reducing the mortality of COVID-19.

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  1. SciScore for 10.1101/2021.01.31.429010: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The primary antibodies include anti-mdig (Invitrogen cat.no. 39-7300), anti-SARS-CoV-2-Spike (Abcam, ab272504), anti-Furin (Abcam, ab183495), anti-TMPRSS2 (Proteintech, cat.no. 14437-1-AP), anti-Cathepsin D (Cell signaling, cat.no. 2284S), and anti-GAPDH (Cell signaling, cat.no. 2118S).
    anti-mdig
    suggested: None
    anti-SARS-CoV-2-Spike
    suggested: None
    anti-Furin
    suggested: (Abcam Cat# ab183495, RRID:AB_2801581)
    anti-TMPRSS2
    suggested: None
    anti-Cathepsin D
    suggested: None
    anti-GAPDH
    suggested: None
    Chromatin immunoprecipitation-sequencing (ChIP-seq): Ten million WT or KO Beas-2B cells were fixed and subjected to ChIP with ChIP-grade antibodies against H3K9me3, H3K27me3, and H3K4me3 (Active Motif, CA)
    H3K9me3
    suggested: None
    H3K27me3
    suggested: None
    H3K4me3
    suggested: None
    To block nonspecific binding of immunoglobulin, slides were incubated with a solution containing 5% goat serum, 0.2% Triton X-100 in PBS for 2 h at room temperature, followed by incubation with primary antibodies against mdig (mouse anti-MINA, Invitrogen with 1:50 dilution) overnight at 4 °C
    anti-MINA
    suggested: None
    Goat anti-mouse biotinylated secondary antibodies were subsequently applied at 1:200 dilution and incubated for 2 h at room temperature.
    anti-mouse biotinylated secondary
    suggested: (Millipore Cat# 21538, RRID:AB_916360)
    Experimental Models: Cell Lines
    SentencesResources
    Cell culture: The human bronchial epithelial BEAS-2B cells were purchased from America Type Culture Collection (
    BEAS-2B
    suggested: BCRJ Cat# 0395, RRID:CVCL_0168)
    Software and Algorithms
    SentencesResources
    Gene set enrichment analyses comparing RNA-seq analyses were performed using the online public database Enrichr (http://amp.pharm.mssm.edu/Enrichr/).
    http://amp.pharm.mssm.edu/Enrichr/
    suggested: (Enrichr, RRID:SCR_001575)
    Pathway analyses were performed by Reactome Knowledgebase (http://www.reactome.org).
    http://www.reactome.org
    suggested: (Reactome, RRID:SCR_003485)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).


    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.


    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).


    Results from JetFighter: We did not find any issues relating to colormaps.


    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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