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

Sang Eric R., Tian Yun, Gong Yuanying, Miller Laura C., Sang Yongming
Genes 2021 v.12 no.2 pp. 154
COVID-19 infection, angiotensin II, biomarkers, disease progression, disease susceptibility, epigenetics, genes, histones, immunopathology, inflammation, interferons, interleukin-6, pathogenesis, promoter regions, vertebrates, virus receptors
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.