Activation of the SARS-CoV-2 receptor Ace2 by cytokines through pan JAK-STAT enhancers

  1. Lothar Hennighausen
  2. Hye Kyung Lee

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Abstract

ACE2, in concert with the protease TMPRSS2, binds the novel coronavirus SARS-CoV-2 and facilitates its cellular entry. The ACE2 gene is expressed in SARS-CoV-2 target cells, including Type II Pneumocytes (Ziegler, 2020), and is activated by interferons. Viral RNA was also detected in breast milk (Wu et al., 2020), raising the possibility that ACE2 expression is under the control of cytokines through the JAK-STAT pathway. Here we show that Ace2 expression in mammary tissue is induced during pregnancy and lactation, which coincides with the establishment of a candidate enhancer. The prolactin-activated transcription factor STAT5 binds to tandem sites that coincide with activating histone enhancer marks and additional transcription components. The presence of pan JAK-STAT components in mammary alveolar cells and in Type II Pneumocytes combined with the autoregulation of both STAT1 and STAT5 suggests a prominent role of cytokine signaling pathways in cells targeted by SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.11.089045: (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

    Experimental Models: Cell Lines
    SentencesResources
    RNA-seq data of human bronchial cell line (BEAS-2B) and airway basal cells from human donors treated with IFNα2, IFNγ, IL4 or IL17A were obtained from GSE148829.
    BEAS-2B
    suggested: None
    Software and Algorithms
    SentencesResources
    ) (version 0.36) and Bowtie (Langmead et al., 2009) (version 1.1.2), with the parameter ‘-m 1’ to keep only uniquely mapped reads, using the reference genome mm10.
    Bowtie
    suggested: (Bowtie, RRID:SCR_005476)
    Picard, http://broadinstitute.github.io/picard/. 2016) was used to remove duplicates and subsequently, Homer (Heinz et al., 2010)
    Picard
    suggested: (Picard, RRID:SCR_006525)
    R and the packages dplyr (https://CRAN.R-project.org/package=dplyr) and ggplot2 (Love et al., 2014) were used for visualization.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    Sequence read numbers were calculated using Samtools (Masella et al., 2016) software with sorted bam files.
    Samtools
    suggested: (SAMTOOLS, RRID:SCR_002105)
    The correlation between the ChIP-seq replicates was computed using deepTools using Spearman correlation.
    deepTools
    suggested: (Deeptools, RRID:SCR_016366)
    RNA-seq analysis: RNA-seq reads were analyzed using Trimmomatic (Bolger et al., 2014)
    Trimmomatic
    suggested: (Trimmomatic, RRID:SCR_011848)
    RNA-seq data shown in Fig. 1b and ChIP-seq data shown in Figure 2 were generated in our lab and deposited in the Gene Expression Omnibus (GEO) and ENCODE.
    ChIP-seq
    suggested: (ChIP-seq, RRID:SCR_001237)
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    ENCODE
    suggested: (Encode, RRID:SCR_015482)

    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 did not find any issues relating to the usage of bar graphs.

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.05.11.089045 on bioRxiv