Epigenetic evolution of ACE2 and IL-6 genes as non-canonical interferon-stimulated genes correlate to COVID-19 susceptibility in vertebrates

Authors: SANG, ERIC - TENNESSEE STATE UNIVERSITY; TIAN, YUN - TENNESSEE STATE UNIVERSITY; GONG, YUANYING - TENNESSEE STATE UNIVERSITY; MILLER, LAURA; SANG, YONGMING - TENNESSEE STATE UNIVERSITY

Submitted to: Genes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2021
Publication Date: 1/25/2021
Publication URL: https://handle.nal.usda.gov/10113/7261464
Citation: Sang, E.R., Tian, Y., Gong, Y., Miller, L.C., Sang, Y. 2021. Epigenetic evolution of ACE2 and IL-6 genes as non-canonical interferon-stimulated genes correlate to COVID-19 susceptibility in vertebrates. Genes. 12(2). Article 12020154. https://doi.org/10.3390/genes12020154.
DOI: https://doi.org/10.3390/genes12020154

Interpretive Summary: The current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. These host factors are subjected to external modifications to DNA that turn genes "on" or "off" also known as epigenetic regulation. These modifications do not change the DNA sequence, but instead, they affect how cells "read" genes by altering DNA accessibility and chromatin structure, thereby regulating patterns of gene expression. Since these host factors are subjected to epigenetic regulation, relevant analyses on some key genes underlying COVID-19 pathogenesis were performed to decipher their epigenetic correlation to COVID-19 susceptibility, namely host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor), and one of the immune messengers, interleukin (IL)-6, a key inflammatory factor in inducing a “cytokine storm”. Interferon-stimulated genes (ISGs) are a group of genes that coordinately combat pathogen invasions, in particular viral infections. We are just beginning to understand there are variety of non-canonical, i.e. unconventional mechanisms, regulating ISG transcription (non-ISGs) in response to interferons (IFNs) and inflammatory stimuli. We showed ACE2 and IL-6 evince active epigenetic regulation via chromatin accessibility across different animal species. This amplifies the pro-inflammatory feedback loop through the IL-6-mediated response and induces greater ACE2 expression, which collectively, may contribute to the occurrence of acute respiratory distress syndrome (ARDS) as in COVID-19. Using our previously reported porcine transcriptome dataset we classified the ISGs and non-ISGs response levels and annotated tentative non-ISGs that share expression patterns similar to IL-6 or ACE2 genes. High expression of non-ISGs could be biomarkers to determine COVID-19 susceptibility and disease development, and partially explain COVID-19 inequality in people of different subgroups.

Technical Abstract: 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. Since these host factors are subjected to epigenetic regulation, we seek to perform relevant analyses on some key genes underlying COVID-19 pathogenesis to longitudinally decipher their epigenetic correlation to COVID-19 susceptibility. We showed that the genes of host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor) and interleukin (IL)-6 (a key immune-pathological factor triggering cytokine storm), evince active epigenetic evolution about 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 recently for their unconventional responses to interferons (IFNs) and inflammatory stimuli through an epigenetic cascade. Furthermore, significantly higher positive histone modification markers and PWM (position weight matrix) 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. Findings characterize ACE2 and IL-6 genes as Non-ISGs that respond differently to inflammatory and IFN signaling from the canonical ISGs and their epigenetic properties may serve as biomarkers to longitudinally predict COVID-19 susceptibility in vertebrates and partially explain COVID-19 inequality in people of different subgroups.