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

Eric R Sang,Yun Tian,Laura C Miller,Yongming Sang

doi:10.3390/genes12020154

Eric R Sang, Yun Tian + Show 2 more

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https://doi.org/10.3390/genes12020154

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Journal: Genes	Publication Date: Jan 25, 2021
Citations: 34	License type: CC BY 4.0

Affiliation: Tennessee State University, National Animal Disease Center

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.

Highlights

Introduction iationsFirst identified in Wuhan, China, December 2019, the novel coronavirus disease 2019(COVID-19) spread worldwide and caused over 0.68 million confirmed deaths and 17 million infected cases across 200 countries by the end of July 2020 [1,2]
After determination of positive histone markers along the IL-6 and angiotensin converting enzyme 2 (ACE2) gene bodies, we examined the existence of cis-regulatory elements (CREs) that interact with typical nonISGs transcription factors, including PU.1
interferon-stimulated gene (ISG) such as those categorized by resemblance to IL-6 and ACE2 genes were sequentially regulated by tumor necrosis factor (TNF), IFN and TLR signaling, which modify chromatin accessibility through activating histone modification and recruitment of transcription factors including PU.1, IRF, and NF-κB binding on the promoter regions of these non-ISGs

Summary

Introduction

Introduction iationsFirst identified in Wuhan, China, December 2019, the novel coronavirus disease 2019(COVID-19) spread worldwide and caused over 0.68 million confirmed deaths and 17 million infected cases across 200 countries by the end of July 2020 [1,2]. COVID-19 stands out as a new zoonotic disease caused by Severe Acute Respiratory Syndrome coronavirus. Higher mortality rates were observed in males than females, and in the patients who have pre-existing medical conditions (comorbidities) regardless of gender or age [6,7,8,9,10,11,12,13,14,15]. These underlying comorbidities include diabetes, cancer, Licensee MDPI, Basel, Switzerland.

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