Abstract
Numerous researches have focused on the genetic variations affecting SARS-CoV-2 infection, whereas the epigenetic effects are inadequately described. In this report, for the first time, we have identified potential candidate genes that might be regulated via SARS-CoV-2 induced DNA methylation changes in COVID-19 infection. At first, in silico transcriptomic data of COVID-19 lung autopsies were used to identify the top differentially expressed genes containing CpG Islands in their promoter region. Similar gene regulations were also observed in an in vitro model of SARS-CoV-2 infected lung epithelial cells (NHBE and A549). SARS-CoV-2 infection significantly decreased the levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) in lung epithelial cells. Out of 14 candidate genes identified, the expression of 12 genes was upregulated suggesting promoter hypomethylation, while only two genes were downregulated suggesting promoter hypermethylation in COVID-19. Among those 12 upregulated genes, only HSPA1L and ULBP2 were found to be upregulated in AZA-treated lung epithelial cells and immune cells, suggesting their epigenetic regulation. To confirm the hypomethylation of these two genes during SARS-CoV-2 infection, their promoter methylation and mRNA expression levels were determined in the genomic DNA/RNA obtained from whole blood samples of asymptomatic, severe COVID-19 patients and equally matched healthy controls. The methylation level of HSPA1L was significantly decreased and the mRNA expression was increased in both asymptomatic and severe COVID-19 blood samples suggesting its epigenetic regulation by SARS-CoV-2 infection. Functionally, HSPA1L is known to facilitate host viral replication and has been proposed as a potential target for antiviral prophylaxis and treatment.
Highlights
MATERIALS AND METHODSIn the last 20 years, an upsurge of several novel pathogenic viral infection outbreaks were identified and reported (de Groot et al, 2013; Weber et al, 2016)
For the first time, we report novel genes that are probably the candidate genes likely to be epigenetically regulated by SARS-CoV-2 infection in lung epithelial and infiltrated immune cells, and those genes might have a role in COVID-19 pathogenesis
The SARS-CoV-2 virus enters the body through the upper respiratory tract and accumulates at the target site of lung tissue triggering series of genetic and epigenetic modifications
Summary
In the last 20 years, an upsurge of several novel pathogenic viral infection outbreaks were identified and reported (de Groot et al, 2013; Weber et al, 2016). For the first time, we report novel genes that are probably the candidate genes likely to be epigenetically regulated by SARS-CoV-2 infection in lung epithelial and infiltrated immune cells, and those genes might have a role in COVID-19 pathogenesis. The candidate DEGs identified from COVID-19 infected lung tissues dataset and are most likely to be epigenetically regulated were searched in this database and are presented as expression heat maps across all the tissues and its expression profile in normal lungs. According to the expression profiling data, DEGs were presented as relative mRNA expression in infected/treated samples compared vs the normal or negative controls were identified using the Limma package (available at5) in Bioconductor package version 1.0.2. Written informed consent was obtained from all study participants before inclusion
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