Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

Abstract

Background: Coronaviruses such as SARS-CoV-2 may circumvent host defence mechanisms by hijacking host proteins, possibly by altering DNA methylation patterns in host cells. While most epigenetic studies have been performed in severely ill COVID-19 patients, studies on individuals who have recovered from mild-to-moderate disease remain scarce. The aim of this study was to assess epigenome-wide DNA methylation patterns in COVID-19 convalescents compared to uninfected controls from before and after the pandemic outbreak began. Methods: DNA was extracted from peripheral blood mononuclear cells originating from uninfected controls before (Pre20, n=5) and after (Con, n=18) 2020, COVID-19 convalescents (CC19, n=14) and symptom-free individuals with a SARS-CoV-2-specific T cell response (SFT, n=6), as well as from Pre20 (n=4) samples stimulated in vitro with SARS-CoV-2. Subsequently, epigenome-wide DNA methylation analyses were performed using the Illumina MethylationEPIC 850K array, and statistical and bioinformatic analyses comprised differential DNA methylation, pathway over-representation and module identification network analyses. Results: DNA methylation patterns of COVID-19 convalescents were altered as compared to uninfected controls, with similar results observed in in vitro stimulations of PBMC with SARS-CoV-2. Differentially methylated genes from the in vivo comparison constituted the foundation for the identification of a possibly SARS-CoV-2-induced module, containing 66 genes of which six could also be identified in corresponding analyses of the in vitro data (TP53, INS, HSPA4, SP1, ESR1 and FAS). Pathway over-representation analyses revealed involvement of Wnt, cadherin and apoptosis signalling pathways amongst others. Furthermore, numerous interactions were found between the obtained differentially methylated genes from both settings and the network analyses when overlaying the data unto the SARS-CoV-2 interactome. Conclusions: Epigenome-wide DNA methylation patterns of individuals that have recovered from mild-to-moderate COVID-19 are different from those of non-infected controls. The observed alterations during both in vivo and in vitro exposure to SARS-CoV-2 showed involvement in interactions and pathways that are highly relevant to COVID-19. The present study provides indications that DNA methylation is one of several epigenetic mechanisms that is altered upon SARS-CoV-2 infection. Further studies on the mechanistic underpinnings should determine whether the observed effects are reflecting host-protective antiviral defence or targeted viral hijacking to evade host defence.

Host’s DNA methylation alterations accompanying COVID-19 infection: a review article

“…Differential DNA methylation profiles differentiate COVID-19 recuperation from uninfected controls. Differential DNA methylation patterns associated with Wnt, mAChRs signaling, and GnRH receptor pathways (Huoman et al, 2021). SARS-CoV-2-negative vs. SARS-CoV-2-positive cases (Spain).…”

Dynamics of Viral and Host 3D Genome Structure upon Infection

“…Comprehensive transcriptomic analysis of multiple infected cell lines and COVID-19 patient-derived samples combined with pathway enrichment analysis implicated over 60 epigenetic response proteins that are relevant to SARS-CoV-2 infection [ 91 ]. Additionally, differential DNA methylation patterns in immune cells that distinguish COVID-19 convalescents from uninfected controls have been reported [ 92 ]. Finally, changes in host 3D chromatin architecture upon SARS-CoV-2 infection have been assessed by in situ Hi-C. Quantification of the pairwise interactions between chromosome regions showed that SARS-CoV-2 infection alters host chromosome organization to induce certain pro-inflammatory genes and suppress antiviral interferon-responsive genes [ 93 ].…”