One of the benefits of personalised medicine is the reduction of lifetime medical or health risks through the use of new emerging preventive medicines and devices combined with lifestyle/behaviour modifications.
The Learna | Diploma MSc Postgraduate Diploma in Genomic Medicine and Healthcare provides a solid foundation in the core concepts of genetics and genomics applied to modern medicine and healthcare.
The course is particularly relevant right now due to the ongoing pandemic and the role of personalised medicine in disease risk evaluation and the prevention of major complications.
Prof. Dr John N. Giannios, Programme Leader for our Postgraduate Diploma in Genomic Medicine and Healthcare, discusses the role of precision genomic medicine, including epigenomics, in the ongoing battle against COVID-19.
Precision Genomic Medicine Systems Including Epigenomics Against COVID-19
The coronavirus-disease 2019 or COVID-19 pandemic is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 or SARS-CoV-2, which consists of a thirty thousand base RNA-genome. The acquired mutagenesis of its spike protein may evade targeted vaccine-coverage, and antibody-therapy due to antigenic-drift causing variants, such as the B.1.351. Thus, deleterious mutations in the virus may arise for adapting to an altered environment that may lead to epigenetic alterations causing resistance to therapeutic and prophylactic approaches.
A solution may become available by facilitating epigenomic-medicine aspects involving nongenomic and genomic factors, which regulate the phenotypic-variation not only in communicable viral infections but also in complex and multifactorial noncommunicable diseases (NCDs), such as cancer, cardiovascular-diseases, diabetes-mellitus, mental-health disorders, chronic respiratory-diseases, musculoskeletal-conditions or obesity.
Lifestyle, metabolic and environmental factors may cause epigenetic alterations which may affect the functional expression, activity and performance of a specific gene without altering the underlying DNA-code in any way. Thus, inside the interactome among the human-host and SARS-CoV-2, epigenetic alterations including chromatin-remodeling, histone-modification, and mainly DNA and RNA methylation may lead to the remodeling and regulation of the expression patterns of the human host.
Another very important factor consists of Epitranscriptomic medicine that involves a powerful linkage of COVID-19 to RNA-modifications including 2-O-me, m6Am or m6A which may affect the life cycle of this RNA-virus, its replication and viral-structure, and mainly innate sensing pathways, and immune responses. Although fortunately this RNA-virus cannot alter genetic-sequence, they are able to alter the EPIGENOME leading to failure of the immune response of the human host spreading the infection rapidly to the upper or lower respiratory system with pneumonia or bronchitis and other organs. Tailored interventions in the interactome among host and viral RNA-modifications may inhibit the life-cycles, and pathogenesis of SARS-CoV-2.
Further work is required for exploring the disease related epigenomic changes at a sequence level, and a scale which is genome-wide leading to the elucidation of the antagonistic pathways against the human host’s immune system. It is very important that epigenomic modifications may eradicate the antiviral pathways of the human host including DNA-methylation which may inhibit the function of antigen presenting cells (APCs), and histone-methylation that may reduce or inhibit immune responses possibly by the mediation of resistant mechanisms, such as the production of proteins resembling the histone tail of the host affecting the transcription initiation complex consisting of RNA polymerase, and transcription factors which may lead to the suppression of the antiviral gene functions.
Furthermore, SARS-CoV-2 may inhibit the host’s recognizing mechanisms, and the expression of interferon-stimulate gene or ISG after the encoding of specific proteins, which are linked to the prevention of responses involving immune signaling. Also, it is possible that SARS-CoV-2 may lead to chromatin-modulation interfering with cytoskeletal regulation of chromatin-dynamics and nuclear-organization, and use signal transduction cascades linked to inflammation, such as the NFKB-pathway, and its downstream signaling pathways including the expression of immunomodulatory-genes for promoting their replication in the human host.
It is up to Genomic Medicine applications to find molecular approaches of inhibiting viral entrance in the host cell, and if there is intracellular entry to find novel gene-targeted approaches for interfering with the differential activation of transcriptional and posttranslational factors, and downstream inflammatory signaling pathways for inhibiting replication, propagation and subsequent pathogenic mechanisms especially in immunocompromised and elderly patients.
With the implementation of Genomic Medicine, we can identify binding sites of the receptors on the cell surface that SARS-CoV-2 is using for entering host cells, such ACE2 and find ways to target genomic variations caused by mutagenesis factors and pathways, such as antigenic-drift or shift, adaptive or RNA-dependent RNA-polymerase (RdRp) mutations changing templates or recombination. Escape-Mutants including N501Y, E484K or K417NIT which may change the structure of RBD in the transmembrane spike-region S of ACE2, they can prevent recognition by immune-cells circumventing binding of antibodies that may lead to enhanced viral infectivity and transmissibility. This requires mRNA vaccine booster-shots covering the new variants.
There is a possibility that overexpression of ACE2 may be linked to epigenetic related demethylation due to enhanced oxidative-stress during infection with SARS-CoV-2. There is also the demethylation possibility of genes regulated by interferon, NFKB and genes encoding cytokines or chemokines and their receptors which might lead to cytokine-storm in immunocompromised and elderly patients. Theoretically, epigenomic medicine by silencing epigenetically ACE2 with epidrugs may contribute to the prevention and/or treatment of COVID-19 and its complications.
Furthermore, hot-spot variants in SARS-CoV-2 may be enriched in IR and CpG-island loci in viral-ORF which may lead to genomic-instability and mutational-drive enhancing viral-transcription and life-cycle. As an epigenetic therapeutic approach for reducing the transcription of the viral-ORF, we may hypermethylate these viral-loci that may limit the progression of COVID-19.
Epigenetics may also regulate methylation involved in the lung infiltration of SARS-CoV-2 and the fusion between the virus and the cell-membrane affecting viral-susceptibility and severity of COVID-19.
The epigenome also includes the effects of noncoding RNA genes, such as miRNAs . Viral-miRNAs which are encoded by SARS-CoV-2 may target specific genes in the human host leading to suppression of its immune-surveillance evading subsequent immune-responses. RNA viruses such as SARS-CoV-2 may produce miRNAs for upregulating the expression of targeted genes in the host enhancing the levels of cellular-apoptosis or type I PCD, inhibiting immunological-responses, and downregulating antiviral pathways of the host.
We may use miRNAs as antiviral epigenomic-tools for circumvention of immune-evasion, and subsequent stimulation of adaptive and innate immune responses leading to the suppression of viral-growth.
More studies involving Gene-Ontology are required for identifying more genes and downstream signaling pathways pathways linked to the infection of SARS-CoV-2, so we can target more actionable genes whose expression may depend upon epigenetic alterations for prevention, diagnosis and treatment under a precision medicine approach based on genomic evidence.
We may upregulate or activate specific miRNAs of the host for silencing the RNA of SARS-CoV-2. Thus, host miRNAs may deregulate viral-pathways leading to the suppression of pathways required for the intracellular entry of SARS-CoV-2, inhibition of evasion of immune-surveillance pathways, prevention of the spreading of virions, and reduction of systemic-symptoms caused from the viral-infection. Ultimately, antagomirs may be used against viral-miRNAs as a therapeutic approach against SARS-CoV-2.
Since the epigenomic modifications are reversible, we may use epidrugs targeting viral-infection pathways, inflammatory responses or apoptosis which may be delivered by nanosystems for SARS-CoV-2 treatment . Furthermore, epigenetic-diet with bioactive natural compounds and vitamins may modify the host epigenome modulating immune-responses inhibiting the activity of SARS-CoV-2, and secondary-infections.
Thus, epigenomic medicine may be implicated in the prevention of SARS-CoV-2 replication, transcription, protein-maturation, entry, cellular immune responses and immune-hyperactivation. Finally, treatment of viral-infection and COVID-19 may be tailored with the combination of pharmacogenomics and pharmacoepigenomics, where the right drugs and/or epidrugs may be administered as a precision medicine approach based on genomic and epigenomic evidence. Furthermore, a 5 P’s systems medicine approach may be implemented by evidence derived from multiomics including transcriptomics, epitranscriptomics, metabolomics, immunogenomics, nutrigenomics, nutriepigenomics, interactomics, proteomics, epiproteomics, and metagenomics for the diagnosis, prevention, targeted-treatment, and prophylactic or therapeutic vaccination for COVID-19 and associated diseases.
Concluding by identifying and reversing disease related epigenetic alterations, we may silence or activate genes involved in the eradication of COVID-19. Also regulation of epigenomic noncoding RNA genes may regulate the expression of protein coding genes, and downstream signaling pathways against COVID-19. The key is to implement Genomic Medicine practice by correlating the clinical phenotype to the disease related genotype for tailoring personalized and precision approaches based on multiomic evidence for screening, diagnosis, prevention, monitoring and therapy for each patient.
Do you want to increase your knowledge of genetic and genome-level diagnostic and predictive testing? Do you want to become a specialist in personalised medicine and improve your clinical management, disease risk evaluation, prevention of major complications and offering the prospect of improved prognosis?