**Abstract**

The outbreak of Coronavirus Disease-2019 (Covid-19), caused by a novel and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2), is a persisting global health concern. Research so far has successfully identified the molecular mechanisms of viral entry, alterations within the host cell upon infection, and the stimulation of an immune response to fight it. One of the most important cellular regulatory machineries within the host cell to be affected by the SARS-CoV-2 infection is epigenetic regulation, which modulates transcriptional activity by DNA sequence-independent factors such as DNA-methylation, RNA interference and histone modifications. Several studies in the literature have previously reported epigenetic alterations within the host due to infections of the Coronaviridae family viruses including SARS-CoV and MERS-CoV that antagonized immune system activation. Recent studies have also identified epigenetic dysregulation of host metabolism by SARS-CoV-2 infection, linking epigenetic mechanisms with the pathophysiology and illness severity of Covid-19. Therefore, this book chapter aims to provide a comprehensive overview of the epigenetic regulation mechanisms in viral infections with a special focus on SARS-CoV-2 infection.

**Keywords:** Coronavirus infection, Covid-19, epigenetic regulation, host repression, immune evasion, cytokine storm, susceptibility

### **1. Introduction**

Coronavirus Disease-2019 (COVID-19), which is caused by a newly emerged, highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2), has been one of the gravest global health concerns of the last century. Previous infections of *Coronaviridae* family, including MERS-CoV and SARS-CoV resulted in human diseases and were associated with the spread of MERS (Middle East respiratory syndrome) and SARS, respectively. SARS-CoV-2 is an enveloped, positive-sense RNA virus. It has a large genome, which consists of six major open reading frames encoding four structural proteins S (spike), E (envelope), M (membrane), N (nucleoprotein) and sixteen non-structural proteins (Nsp1–16).

Epigenetic mechanisms are vital for the regulation of transcriptional activity. Alterations within the epigenetic landscape affect gene expression via influencing chromatin accessibility rather than changing the underlying DNA sequence. Therefore, epigenetic modifications provide a reversible and flexible mechanism of directing cellular function in response to environmental stimuli. Viral infections

**Figure 1.**

*Summary of the interplay between the host epigenetic regulation machinery and viral infections.*

are important sources of such stimuli that cause drastic changes in the gene expression patterns of the host. While epigenetic reprogramming ensures transcriptional activation that is required for the induction of a proper immune response against viral infections, factors of the epigenetic regulation mechanisms are also hijacked by viruses to subvert the host antiviral defense machinery. This establishes a bidirectional relationship between the host cell and the virus, as depicted in **Figure 1**, controlling the viral life cycle and the dysregulation of the host gene expression [1].

Herein, we unfold the complex regulatory pathways of epigenetic mechanisms affecting the host cell and the virus. Particularly, we discuss the epigenetic basis of viral entry and cytokine storm induction in relation to SARS-CoV-2 infection, as well as epigenetic susceptibility to Covid-19 from a molecular point of view.

#### **2. Epigenetic regulation mechanisms**

Epigenetics was first introduced to the scientific community as a term to describe the molecular mechanisms that cause heritable phenotypic changes, which are independent of the genetic material [2]. Since then, regulation of DNA accessibility through chromatin condensation has been identified as the main mechanism of epigenetic regulation, implicating them in several cellular processes like cell cycle, cellular proliferation, transcriptional memory, and DNA damage repair [3]. The level of chromatin compaction in a given genomic locus determines its transcriptional activity as genes within the loosely packaged euchromatin regions are actively transcribed and the highly condensed heterochromatin regions are transcriptionally silent [4]. The interplay between euchromatin and heterochromatin enables the establishment of differential gene expression patterns and is essentially regulated by epigenetic mechanisms involving DNA methylation, non-coding RNAs and RNA interference (RNAi), DNA replication-independent incorporation of histone variants and histone post-translational modifications (**Figure 2**).

In eukaryotic cells, chromatin condensation is achieved by packaging the DNA into chromatin by wrapping the naked DNA onto octamers of core histones H2A, H2B, H3, and H4 [5]. Deposition of the linker histone H1 leads to the formation of higher-order chromatin and is associated with transcriptional silencing [6]. Histones can be covalently modified by the post-translational addition of a variety of functional groups including but not limited to methyl-, acetyl-, phosphoryl-, ubiquitin and ADP-ribose that altogether constitute an epigenetic signature of transcriptional activity [7]. Histone acetylation is generally associated with an

*Epigenetic Regulation Mechanisms in Viral Infections: A Special Focus on COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.98866*

**Figure 2.**

*The conformational transition between euchromatin and heterochromatin is mediated by epigenetic mechanisms.*

open chromatin conformation and active gene expression. H3K9ac, H4K16ac and H3K27ac are the most abundant histone acetylations found at the promoters and enhancers of actively transcribed genes [8, 9]. On the other hand, the impact of histone methylations on gene expression strictly depends on their degree and location. For instance, H3K4me1–2-3 and H3K9me are marks of active transcription sites, while H3K9me2–3 and H3K27me2–3 are found in heterochromatin and are indicators of repressed gene state [10].

The main constituents of nucleosomes are canonical histones and share only a certain level of similarity with their corresponding "replacement" variants. These differences in amino acid sequence affects gene expression both by causing conformational alterations of chromatin and disruption of existing interactions between histones and their chaperons, while establishing new ones (reviewed in [11]). Histone variants are involved in several chromatin-related processes such as transcriptional regulation (H3.3 and macroH2A), DNA damage signaling (H2A.X), nucleosome positioning (H2A.Z) and the formation of centromeres (CENP-A).

RNA interference (RNAi) is another mechanism of epigenetic regulation that facilitates heterochromatin formation and transcriptional silencing by the action of non-coding RNAs. X chromosome inactivation is a significant example of RNAi mediated transcriptional repression, which results in the random heterochromatinization and silencing of one of the X chromosomes in females to provide dosage compensation [12]. X-inactivation is initiated by the long non-coding RNA Xist (X-inactive specific transcript) and via the recruitment of histone modifiers and corepressor complexes, an inactive gene state throughout the X chromosome is achieved [13]. Furthermore, small non-coding RNAs including micro-RNAs (miR-NAs), small interfering-RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs) are important contributors of transcriptional regulation mediated by RNAi [14–17].

DNA methylation is a reversible post-translational modification of DNA that cause repression of gene expression when present at CpG islands in promoter regions. CpG denotes cytosine residues followed by a guanine nucleotide, where the methyl-group is covalently attached to the 5th carbon of cytosine, giving rise to 5-methylcytosine (5mC). DNA methylation is catalyzed by DNMT enzymes in mammals. 5mC marks that the *de novo* DNA methyltransferases DNMT3A and DNMT3B set during embryonic development are inherited in every cell division semi-conservatively [18] and the maintenance DNA methyltransferase DNMT1 methylates the newly synthesized, hemi-methylated strand [19]. Heterochromatin exhibits high levels of 5mC that correlates with lower levels of gene expression led by transcriptional silencing [20, 21].

Recent studies identified a number of RNA modifications that play a wide range of regulatory roles in various cellular processes and embryonic development. The list of RNA modifications comprises of N7-methylguanosine (m7G), 2′-O-methylation (Nm), 5-methyl cytosine (m5C), N1-methyladenosine (m1A), N6-methyladenosine (m6A), and 3-methylcytidine (m3C). All these epigenetic modifications of RNA constitute a complex regulatory network over several aspects of mRNA metabolism such as translation efficiency, mRNA splicing and nuclear export [22].
