Epigenetic Evolution of ACE2 and IL-6 Genes: Non-Canonical Interferon-Stimulated Genes Correlate to COVID-19 Susceptibility in Vertebrates

  1. Eric R. Sang
  2. Yun Tian
  3. Laura C. Miller
  4. Yongming Sang

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Abstract

The current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. These host factors are subjected to epigenetic regulation; therefore, relevant analyses on some key genes underlying COVID-19 pathogenesis were performed to longitudinally decipher their epigenetic correlation to COVID-19 susceptibility. The genes of host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor) and interleukin (IL)-6 (a key immuno-pathological factor triggering cytokine storm) were shown to evince active epigenetic evolution via histone modification and cis/trans-factors interaction across different vertebrate species. Extensive analyses revealed that ACE2 ad IL-6 genes are among a subset of non-canonical interferon-stimulated genes (non-ISGs), which have been designated for their unconventional responses to interferons (IFNs) and inflammatory stimuli through an epigenetic cascade. Furthermore, significantly higher positive histone modification markers and position weight matrix (PWM) scores of key cis-elements corresponding to inflammatory and IFN signaling, were discovered in both ACE2 and IL6 gene promoters across representative COVID-19-susceptible species compared to unsusceptible ones. The findings characterize ACE2 and IL-6 genes as non-ISGs that respond differently to inflammatory and IFN signaling from the canonical ISGs. The epigenetic properties ACE2 and IL-6 genes may serve as biomarkers to longitudinally predict COVID-19 susceptibility in vertebrates and partially explain COVID-19 inequality in people of different subgroups.

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  1. Version published to 10.3390/genes12020154
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    SciScore for 10.1101/2020.09.09.273268: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Annotation of ENCODE epigenetic datasets: The profile of epigenetic markers relevant to histone positive modification, mainly H3K4me3 and H3K27ac, were searched using the gene symbols through the ENCODE public domain at https://www.encodeproject.org/ under the default condition [55].
    https://www.encodeproject.org/
    suggested: (HapMap 3 and ENCODE 3, RRID:SCR_004563)
    The ENCODE datasets for generating the epigenetic results include those mainly based on Chip-Seq and ATAC-Seq from 839 and 157 cell/tissue types of humans and mice, respectively.
    ENCODE
    suggested: (Encode, RRID:SCR_015482)
    Promoter sequence extraction and alignment: The DNA sequences of the proximal promoters of analyzed genes were extracted from NCBI Gene and relevant databases (https://www.ncbi.nlm.nih.gov/gene).
    https://www.ncbi.nlm.nih.gov/gene
    suggested: (Entrez Gene, RRID:SCR_002473)
    In most cases, the annotations were double verified through the same Gene entries at Ensembl (https://www.ensembl.org).
    Ensembl
    suggested: (Ensembl, RRID:SCR_002344)
    https://www.ensembl.org
    suggested: (Homologous Sequences in Ensembl Animal Genomes, RRID:SCR_008356)
    The protein and DNA sequences were aligned using the multiple sequence alignment tools of ClustalW or Muscle through an EMBL-EBI port (https://www.ebi.ac.uk/).
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)
    Muscle
    suggested: (MUSCLE, RRID:SCR_011812)
    https://www.ebi.ac.uk/
    suggested: (European Bioinformatics Institute, RRID:SCR_004727)
    Other sequence management was conducted using programs at the Sequence Manipulation Suite (http://www.bioinformatics.org).
    http://www.bioinformatics.org
    suggested: (Bioinformatics Organization, RRID:SCR_012008)
    Sequence alignments were visualized using Jalview (http://www.jalview.org) and MEGAx (https://www.megasoftware.net).
    Jalview
    suggested: (Jalview, RRID:SCR_006459)
    The regulatory elements (and corresponding binding factors) in the ~2.5 kb proximal promoter regions were examined against both human/animal TFD Database using a program Nsite (Version 5.2013, at http://www.softberry.com).
    http://www.softberry.com
    suggested: (SoftBerry, RRID:SCR_000902)
    For topological comparison between phylogenic trees generated using IL-6 and ACE2 gene proximal promoters, the phylogenies of Newick strings were generated using the MEGA program, and topological comparison between the Newick trees was performed with Compare2Trees at (http://www.mas.ncl.ac.uk/~ntmwn/compare2trees) to obtain the overall topological scores.
    MEGA
    suggested: (Mega BLAST, RRID:SCR_011920)
    RNA-Seq and data analysis: For expression confirmation, several sets of RNA-Seq data from NCBI Gene databases, and one of ours generated from porcine alveolar macrophages (BioProject with an accession number of SRP033717), were analyzed for categorizing ISGs and non-ISGs accordingly to the expression patterns of IL-6 and ACE2 genes.
    NCBI Gene
    suggested: None
    BioProject
    suggested: (NCBI BioProject, RRID:SCR_004801)
    Significantly and differentially expressed genes (DEGs) between two treatments were called using an edgeR package and visualized using bar charts (RPKM) or heatmaps (Log2 fold ratio) as previously described [57].
    edgeR
    suggested: (edgeR, RRID:SCR_012802)

    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.

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  3. Version published to 10.1101/2020.09.09.273268v1 on bioRxiv