What is epigenetics used for

At the same time, KSHV lytic replication induces a dynamic reprogramming of the viral epitranscriptome itself [ 72 ]. Specifically, analyzing 5mC content across various RNAs, they observed consistent methylation patterns in corresponding genomic positions of different RNAs, suggesting that the methylation of coronavirus RNAs is sequence-specific or controlled by RNA structural elements [ 73 ].

Table 1 summarizes the epigenetic implication in viral infection and their functional outcomes. In recent years, epigenetics evolved quickly, giving us better knowledge about inheritability functions, memory mechanisms, and developmental biology. The studies into the human epigenome are becoming more relevant in oncology, immunology, and infectious diseases [ 74 , 75 ].

Indeed, during the last decade, the epigenetic research provided evidence that DNA and RNA viruses developed functions that antagonize the regulatory machine of the host epigenome by altering the host metabolism and gene expression, setting up a permissive environment for virus replication and spread [ 76 , 77 ].

Furthermore, there is much evidence indicating that age-related changes to the host epigenome might compromise immune cell composition and function, affecting viral defenses, including the adaptive immune response [ 10 , 12 ].

Evaluating the DNA methylation age of immune cells and other blood cell types before, during, and after infection could help explain how the aged epigenome impacts disease severity and how the virus alters the aged epigenome [ 10 ]. The vulnerability of the elderly to SARS-CoV-2 may also have to do with the effect of the epigenome on viral entry [ 78 ]. This process is initiated on the cell surface by physical interaction between the viral spike glycoprotein receptor, the ACE2 protein [ 26 ], and a co-receptor, the dipeptidyl peptidase-4 DPP4 [ 30 ].

Nowadays, there are no specific antiviral drugs against COVID infection yet, and vaccines are still under development. Even so, many potential therapeutic approaches are under investigation, and more research is urgently needed to identify effective vaccines and safe drugs for treating COVID infections in order to develop pre- and post-exposure treatments against the pathogen.

Although the first aim would be generating SARS-CoV-2 S-based vaccines, with conserved epitopes, able to elicit broadly neutralizing antibodies or virus-specific T cell responses, the identification, and development of safe and effective drugs to overcome SARS-CoV-2 entry and replication is essential. Epigenetic research might help to accomplish these tasks thanks to a better understanding of the mechanisms involved in viral chromatin modification in lytic viruses and about host-virus interactions, including genetic factors that contribute to the protective or pathogenic host responses.

Clinical trials, FDA approved epigenetic-targeted agents, and combination therapy of epigenetic and antiviral drugs is currently considered as useful and beneficial for viral replication impairment and the control of the host immune response [ 83 ]. Remarkably, pharmacokinetic and pharmacodynamic properties of antivirals may also be influenced by epigenetic regulation, highlighting, once again, their relevance in the treatment SARS-CoV-2 infection [ 84 ]. Recently, El Baba and coworkers analyzed several epigenetic mechanisms involved in coronaviruses infections, identifying some major epigenetic player which can be therapeutically targeted [ 83 ].

Indeed, many of the nonstructural proteins involved in viral transcription, replication, and maturation processes are regulated by different classes of HDACs, implying that HDAC inhibitors, such as Vorinostat or suberanilohydroxamic acid SAHA , combined with antivirals, might be useful tools to interfere with these processes [ 85 , 86 ]. Of note, previous studies already showed that ACE2 expression is regulated by DNA methylation and histone modifications. Therefore, DNMT1 inhibitors, e.

Moreover, knowing that viruses depend on the host epigenetic machinery, epigenetic drugs already used in cancer therapies might be exploited for their broad-spectrum antiviral action and inflammatory control [ 83 , 90 ]. Indeed, some evidence indicated that the main culprit behind COVID deaths is the cytokine storm, characterized by an uncontrolled over-production of soluble markers of inflammation. Interestingly, the polycomb repressive complex 2 PRC2 , which mediates transcription repression via H3K27me3 enrichment at specific IFN-stimulated genes, could also be considered a target.

Pharmacologic inhibitors of PRC2 are currently in advanced clinical trials for cancer treatment and could be easily repurposed to treat COVID patients [ 91 ]. Recent studies show that innate immune cells may possess a form of memory, termed Trained Immunity TRIM , a long-term boosting of innate immune response mainly maintained by natural killer cells and lung innate lymphoid cell group 2 through common epigenetic mechanisms [ 92 , 93 ].

The exposure to an initial stimulus leads these cells to a metabolic, mitochondrial, and epigenetic reprogramming, which results in a memory phenotype of enhanced immune responses after the exposition to a secondary, heterologous stimulus [ 94 ]. Geller et al.

Recent studies also propose vitamins and natural products, as epigenetic modifiers, to enhance immunity and reduce the inflammatory response in COVID patients [ 95 , 96 , 97 ]. RNA-based drugs are other epigenetic tools that should be investigated for treating viral infections [ 99 , ].

Indeed, the design of antisense oligonucleotides, such as Miravirsen, under investigation for HCV treatment, could be used to inhibit viral replication by scavenging miRNAs that are involved in the process [ , ]. Figure 2 summarizes some of the epigenetic targets and interventions potentially useful for Coronavirus viral infections treatment.

Coronavirus-dependent host epigenome alterations and potential interventions. Viruses, like those from the Coronaviridae family, can alter the host epigenome, negatively affecting the host immune response and successfully spreading the infection. The immune response is extensively regulated by specific epigenetic marks, such as chromatin remodeling, histone modification, DNA, and RNA methylation. The epigenetic machinery is responsible not only for the host response priming and memory, but also for ensuring its functional regulation.

Age-related alterations to the host epigenome might affect the adaptive immune response, hindering viral defenses.

Epigenomics represent a powerful tool to explore how to prevent, attenuate, or reverse the viral infection therapeutically. The enzymes responsible for the epigenetic alterations might represent potential targets for new antiviral drugs.

Noteworthy, thanks to sophisticated bioinformatics software, we are now able to visualize and interpret the epigenomic data, providing in-depth cell-specific knowledge about the genetic and epigenetic predispositions of an individual and explaining how the environment affects the function of our genes by leaving long-term marks on the genome. Indeed, epigenome mapping, together with EWAS and GWAS studies, provides us with tools in the diagnostics of many common human diseases, indicating that these studies could be employed for individual diagnosis and personalized therapies [ , ].

Above all, the enzymes responsible for the epigenetic alterations represent an exciting field for discovering new drug targets. The COVID pandemic is one of the most serious global health threats of the contemporary age so far.

The presence of the so-called cytokine storm induced by the virus leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death.

Epigenomic studies might open new avenues for developing antiviral drugs by evaluating specific epigenetic modulators as targets and exploring new chromatin-based therapies for different virus families, including Coronaviruses, which could reveal fundamental new landscapes of virus—host interaction and their role in disease severity [ 85 ]. Previous works focused on specific epigenetic mechanisms [ 83 , ]. This article summarizes the comprehensive knowledge about epigenetic aspects associated with SARS-CoV-2 infection and suggests potential epigenetically based therapies.

In particular, from this analysis, it emerges that understanding the epigenetic regulation underlying the immune response to SARS-CoV-2 will help to design and develop novel specific strategies to prevent and treat the infection.

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Non-coding RNA Res. Rett syndrome has symptoms that include intellectual disabilities. The symptom of alpha-thalassaemia one case is anemia. Various cancers have different symptoms and etiologies. For instance, some cancers have symptoms that include microsatellite instability.

Their etiologies involve de novo methylation of the MLH1 gene. Some cancers have symptoms that include disruption of Rb and the p53 pathway, and uncontrolled proliferation. Their etiologies involve de novo methylation of various gene promoters.

Their etiologies involve loss of imprinting. Leukemia has symptoms that include disturbed hematopoiesis. Rubinstein—Taybi syndrome has symptoms that include intellectual disabilities. Its etiology involves mutation in CREB-binding protein histone acetylation.

Coffin—Lowry syndrome has symptoms that include intellectual disabilities. Its etiology involves mutation in Rsk-2 histone phosphorylation. Disrupting any of the three systems that contribute to epigenetic alterations can cause abnormal activation or silencing of genes. Such disruptions have been associated with cancer , syndromes involving chromosomal instabilities, and mental retardation Table 1. The first human disease to be linked to epigenetics was cancer, in Because methylated genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin.

On the other hand, too much methylation can undo the work of protective tumor suppressor genes. However, there are stretches of DNA near promoter regions that have higher concentrations of CpG sites known as CpG islands that are free of methylation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off.

This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer Egger et al. Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more common in human cancer than DNA sequence mutations Figure 2.

Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation.

Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH1 can make a microsatellite unstable and lengthen or shorten it Figure 2.

Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome , one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4, males and 1 in 8, females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and "autistic-like" behavior Penagarikano et al.

Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable Figure 3.

The syndrome is caused by an abnormality in the FMR1 fragile X mental retardation 1 gene. However, individuals with over repeats have a full mutation , and they usually show symptoms of the syndrome.

This methylation turns the gene off, stopping the FMR1 gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome.

Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMR1 methylation is the real syndrome culprit. Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes.

Because so many diseases, such as cancer, involve epigenetic changes, it seems reasonable to try to counteract these modifications with epigenetic treatments. These changes seem an ideal target because they are by nature reversible, unlike DNA sequence mutations.

The most popular of these treatments aim to alter either DNA methylation or histone acetylation. Inhibitors of DNA methylation can reactivate genes that have been silenced. These medications work by acting like the nucleotide cytosine and incorporating themselves into DNA while it is replicating. Drugs aimed at histone modifications are called histone deacetylase HDAC inhibitors. Blocking this process with HDAC inhibitors turns on gene expression.

Caution in using epigenetic therapy is necessary because epigenetic processes and changes are so widespread. To be successful, epigenetic treatments must be selective to irregular cells; otherwise, activating gene transcription in normal cells could make them cancerous, so the treatments could cause the very disorders they are trying to counteract.

Despite this possible drawback, researchers are finding ways to specifically target abnormal cells with minimal damage to normal cells, and epigenetic therapy is beginning to look increasingly promising. Egger, G. Epigenetics in human disease and prospects for epigenetic therapy. Nature , — doi Feinberg, A. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature , 89—92 doi Jones, P. The fundamental role of epigenetic events in cancer.

Nature Reviews Genetics 3 , — doi Kaati, G. Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. European Journal of Human Genetics 10 , — Penagarikano, O. The pathophysiology of fragile X syndrome. Annual Review of Genomics and Human Genetics 8 , — doi Robertson, K. DNA methylation and chromatin: Unraveling the tangled web.

Oncogene 21 , — doi Epigenetic Influences and Disease. Birth Defects: Causes and Statistics. Another common epigenetic change is histone modification. Histones are structural proteins in the cell nucleus. DNA wraps around histones, giving chromosomes their shape.

Histones can be modified by the addition or removal of chemical groups, such as methyl groups or acetyl groups each consisting of two carbon, three hydrogen, and one oxygen atoms. The chemical groups influence how tightly the DNA is wrapped around histones, which affects whether a gene can be turned on or off. Errors in the epigenetic process, such as modification of the wrong gene or failure to add a chemical group to a particular gene or histone, can lead to abnormal gene activity or inactivity.

Altered gene activity, including that caused by epigenetic errors, is a common cause of genetic disorders. Conditions such as cancers, metabolic disorders, and degenerative disorders have been found to be related to epigenetic errors. Scientists continue to explore the relationship between the genome and the chemical compounds that modify it. In particular, they are studying the effects that epigenetic modifications and errors have on gene function, protein production, and human health.

Other chapters in Help Me Understand Genetics.