Epigenetic mechanisms regulating COVID-19 infection

Abstract

Coronavirus disease 2019 (COVID-2019) outbreak originating in December 2019 in Wuhan, China has emerged as a global threat to human health. The highly contagious SARS-CoV-2 infection and transmission presents a diversity of human host and increased disease risk with advancing age, highlighting the importance of in-depth understanding of its biological properties. Structural analyses have elucidated hot spots in viral binding domains, mutations, and specific proteins in the host such as the receptor angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS2) to be implicated in cell entry and viral infectivity. Furthermore, epigenetic changes that regulate chromatin structure have shown a major impact in genome stabilization and maintenance of cellular homoeostasis and they have been implicated in the pathophysiology of the virus infection. Epigenetic research has revealed that global DNA methylation along with ACE2 gene methylation and post-translational histone modifications may drive differences in host tissue-, biological age- and sex-biased patterns of viral infection. Moreover, modulation of the host cells epigenetic landscape following infection represents a molecular tool used by viruses to antagonize cellular signalling as well as sensing components that regulate the induction of the host innate immune and antiviral defence programmes in order to enhance viral replication and infection efficiency. In this review, we provide an update of the main research findings at the interface of epigenetics and coronavirus infection. In particular, we highlight the epigenetic factors that interfere with viral replication and infection and may contribute to COVID-19 susceptibility, offering new ways of thinking in respect to host viral response.

Keywords: ACE2; COVID-19; DNA methylation; X-linked genes; histone PTMs; virus infection.

Figure 1.

(a) Schematic representation of the coronavirus structure indicating the viral surface proteins (spike, membrane, envelop) embedded in lipid bilayer envelop, the RNA and the nucleocapsid ribonucleoproteins. (b) Genomic organization of SARS-CoV-2 spike protein indicating the receptor-binding domain (RBD), the receptor-binding motif (RBM) and heptad repeats 1, 2 (HR1, 2). The protease site (at 687) is also shown that can be cleaved to generate the S1 and S2 subunits. TM: transmembrane. (c) Schematic representation of the ACE2 protein indicating the peptidase and collectrin domains. (d) Upper panel: Linear schematic of ACE2 gene (not shown to scale) showing exons in green boxes and introns as a horizontal blue line. The location of CpG (cg085599149) near the ACE2 transcription start site that is hypomethylated during ageing [30] and the marks of histone methylation and acetylation [22] are shown. Bottom panel: ACE2 protein indicating the zinc metallopeptidase (HEXXH motif) and collectrin domains along with the key glycan (glycosylated asparagine at position 90) that is implicated in SARS-CoV-2 spike binding