Dear Editor,
In the current century, ecological disasters and upcoming crises, such as COVID-19 or mpox, highlight how epigenetic modifications may influence viral infectivity and disease severity. The interaction between humans and animals—both domestic and wild animals—is the primary cause of the development and spread of epidemic diseases. We can claim that general environmental factors can aid or hinder the transmission of the virus based on the lessons we have learned from the COVID-19 era and its environmental effects. Epigenomics seeks to provide knowledge about and protect against emerging ecological disasters and epidemics in the 21st century [1].
Moura et al. [2] studied the effect of epigenetic variation on the severity of the COVID-19 disease. They revealed how the newly discovered DNA methylation landscape affects the severity of progressive disease and is related to host immune function. Oncology biomarkers are employed in malignancies or viral infections that affect the adaptive immune system and are regulated by DNA methylation alterations, such as HPV, HBV, EBV, KSHV, HIV, and COVID-19. The efficacy of the vaccination may be impacted by the variations of this and other genes [3].
The network of epigenetics is an understanding of the mechanisms that affect metabolic alterations in differentiation. During evolutionary transitions, the purpose of metabolism-homeostasis has been shifted from housekeeping to regulating cellular cycles during growth. As donors, substrates, cofactors, and antagonists of epigenetic modifying complexes and epigenetic modifications, metabolites such as S-adenosylmethionine, acetyl-CoA, ketoglutarate, 2-hydroxyglutarate, and butyrate do act. The new findings on the significance of metabolites produced by B cells, macrophages, and specific CD4+ T cell subsets on metabolism support the theory that metabolism is a dynamic process (Table 1 ). Large enhancers, called super-enhancers, play a key role in epigenetic gene regulation. The high number of potential regions of histone modifications compatible with super-enhancer elements, which include H3K4me1 and H3K27 acetylation (H3K27Ac), are enriched in transcription factor binding motifs for T cells. Disease-related genetic variation is frequently seen in regions with identified super-enhancers. Notably, only cell types linked to disease pathology are enriched for illness-associated single-nucleotide polymorphisms (SNPs) in locations with active enhancer modifications [4].
Table 1.
Viral infections that affect similar pathophysiological processes like aging, neurodegeneration, cancer, and inflammation are regulated by conserved epigenetic pathways.
| DNA methylation |
histone modifications |
ncRNAs |
|---|---|---|
| Outcomes | ||
| Aging | Neurological condition | Cancer and Inflammation |
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To create epigenetic conditions that control cell differentiation programs, histone methyltransferases and DNA methyltransferases are both crucial. The one-carbon metabolic pathway generates S-adenosylmethionine (SAM), which serves as a methyl donor for DNA methyltransferase (DNMT) complexes and the lysine and arginine histone methyltransferases. The folate and methionine cycles are both involved in one-carbon metabolism. Developmental disorders and aberrant methylation states in cancer are linked to mutations in this pathway's enzymes. SAM functions as a universal methyl donor and is required by all histone methyltransferase complexes. The most responsive histone methylation alteration to changes in the cell's SAM content and one-carbon metabolic pathway appears to be the H3K4me3 modification. The SAM metabolite also functions as a methyl donor for DNA methylation modification. DNA methylation often occurs at a CpG dinucleotide's 5-carbon cytosine residue (5 mC). CpG is a significant epigenetic alteration that influences transcription factors' ability to bind to their DNA-binding elements and to recruit proteins with methyl-binding domains. In mammalian cells, three DNMTs have been found. Importantly, abnormal DNA methylation patterns are frequently observed in illnesses like cancer, which disrupt cellular differentiation programs [5].
Molecular mechanisms control viral-host interactions such as virus entry, replication and transcription, escape, and immune system control. Epigenetics can detect viral infections and limit or change gene expression. Epigenetic therapies are a desirable and effective strategy for limiting viral replication and inflammatory gene expression. One of the most effective ways to prevent the spread of new viral infections is to expand the treatment options by developing epigenetic medicines. Histone deacetylases (HDACs) appear to be an important epigenetic target for viral infection therapy [6]. As a result, antiviral drugs based on class III HDACs, such as resveratrol and sirtuin-1 (SIRT1), have already been identified. Epigenetic treatments must be initiated immediately to prevent or reduce acute respiratory distress syndrome (ARDS) and the increased mortality caused by a cytokine storm. Cytokine storm syndrome is treatable with anti-cytokine therapies. When histone methyltransferase G9a binds to the tumor necrosis factor (TNF) promoter on H3K9, DNA methylase DNMT3a/b is activated, putting the TNF-alpha promoter into a transcriptional repressor state and lowering TNF-alpha protein levels. Histone acetylation (H3K9ac, H3K36ac, and H4K5ac) reduces IL-8 and TNF-alpha levels, which are primarily produced in response to viral infection. The broad-spectrum HDACi TSA inhibited the synthesis of these pro-inflammatory mediators (Fig. 1 ). There is compelling evidence that bacterial-viral co-infections increase pathogenicity. Epigenetic modification in multimicrobial interactions may be a broadly applicable principle that benefits a wide range of diseases. New data on the epigenetic regulation of HIV and herpesviruses by bacteria and other microbial infections supports this idea [7].
Fig. 1.
The various epigenetic targets and their regulation (DNMT, HDM, HDAC, and HMT) demonstrate the epigenetic landscape during viral replication. When some epigenetic targets are suppressed, the load of viral replication is reduced. As a result, it is an important therapeutic approach for viral infection. Several viral pathogen interactions take place throughout the body. Viral pathogens can enter the body through skin contact, food or water consumption, or inhalation. Abnormal genetic changes (DNA methylation, histone modifications, and ncRNAs) influence a cell's ability to maintain homeostasis, corresponding to intricate epigenetic signatures. They also play an important role in cell transformation. The pathogenesis can be accelerated when bacteria and viruses coexist in the same niche. One recognized way a bacterial infection can affect viral infection is through epigenetic changes.
Additional research could reveal host and viral molecular levels that are important for disease progression, leading to the development of novel, highly effective medicines that target a variety of infections. Without understanding the environmental conditions that control essential viral epigenetic alterations, our ability to eliminate virus-associated infections is limited. In summary, epigenetics advances our understanding of human immunology in disease. Integrating information from metabolism-induced immune responses and epigenetics, we believe, will be a challenge for the next generation of researchers studying re-emerging viruses.
CRediT authorship contribution statement
Maryam Shafaati: Conceptualization, Data Curation, Writing - Original Draft, Writing - review & editing. Milad Zandi: Conceptualization, Data Curation, Writing - Original Draft, Writing - review & editing. Priyanka: Conceptualization, Data Curation, Writing - Original Draft, Writing - review & editing. Om Prakash Choudhary: Conceptualization, Data Curation, Supervision, Writing - Original Draft, Writing - review & editing. All authors critically reviewed and approved the final version of the manuscript.
Ethical approval
This article does not require any human/animal subjects to acquire such approval.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
All authors report no conflicts of interest relevant to this article.
Acknowledgments
Fig. 1 has been created with BioRender (https://biorender.com/). The authors are thankful to their respective institutions/universities for the completion of this work.
References
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