The Future of Epigenetics

By Michael Greenwood, M.Sc.Reviewed by Emily Henderson, B.Sc.

Epigenetics is the study of changes in gene expression that can result in a differing phenotype without changing the DNA sequence of the genome.

Epigenetics. Image Credit: kentoh/Shutterstock.com

Epigenetic changes are heritable and behave as a regulatory mechanism that influences gene translation rates based on exogenous cues such as availability of nutrition and overall health, alongside stress and other psychological factors, both prenatally and postnatally.

Cell types are differentiated by function early in embryonic development via the epigenome, acting on molecular cues to promote or suppress the expression of particular genes in the relevant cells. Most epigenetic modifications take the form of DNA methylation, histone modification, or utilize RNA to silence genes.

Epigenetics and disease

Many diseases influence or are influenced by the epigenome, and research efforts are focused on deciphering these changes as early disease indicators or in search of preventative or correcting drug leads. SARS-CoV-2, for example, has been implicated in disrupting the epigenetic network, resulting in antagonism of the host immune system.

Other viruses such as H3N2 influenza and hepatitis C have been demonstrated to mimic histones and thereby interact with the transcription complex, consequently antagonizing the production of interferon by preventing the transcription of interferon promoting genes. DNA methylation events have also been observed upon infection with MERS-CoV and H5N1 influenza, resulting in the loss of antigen presentation molecules and blunting of the immune response.

Genetic diseases with origins in impaired epigenetic pathways include various immunodeficiencies, asthma, many cancers, and several specific disorders such as Fragile X syndrome, Angelman’s syndrome, and Prader-Willi syndrome. Each of these is the result of upregulated or downregulated gene expression by hyper/hypomethylation or histone acetylation, modulated by the epigenome.

For example, multiple sclerosis is the result of hypermethylation of the FOXP3 gene and hypomethylation of PAD2, resulting in altered myelin processing, while hypermethylation resulting in reduced expression of the glucocorticoids has been implicated in depression.

Epigenetic drugs

Epigenetic therapies have shown potential against several diseases that are influenced by epigenetic changes. Azanucleosides are considered the first true epigenetic drugs, having first been synthesized in the 1960s and consisting of pyrimidine analogs.

Among the mechanisms of action identified for these drugs, they generally cause hypomethylation by inhibiting the responsible methyltransferase enzymes. It is also thought that the drugs inhibit RNA-based methylation and are capable of inducing specific immune responses for the treatment of some cancers, mainly by upregulating endogenous retroviruses following methylation inhibition, promoting interferon production.

Histone modifier drugs are also in development; these prevent the removal of acetyl groups from DNA to maintain gene expression: histone deacetylase inhibitors. These drugs have had a history as mood stabilizers and anti-epileptics, though are now under investigation as cancer therapeutics in place of or combination with several traditional chemotherapeutics.

In the future, these drugs have the potential to reactivate silenced tumor suppressor genes and silence tumor-promoting genes, though at this stage the specificity towards target cancer cells is low, and inducing epigenetic changes in non-target cells raises numerous safety concerns. Additionally, they are often quickly degraded by enzymes in vivo, and present low retention time in the body.

Nanoparticle drug delivery systems may be the solution to the poor pharmacokinetic profile of epigenetic drugs, exhibiting long retention time, good bioavailability, and the potential for passive and active targeting strategies towards sites of inflammation such as the tumor parenchyma.

These inflamed sites often display disorganized and fenestrated blood vasculature in which nano-sized objects tend to accumulate in the case of passive targeting, in a phenomenon known as the enhanced permeability and retention effect which accounts for the passive targeting aspect of nanoparticles.

However, this effect is highly dependent on the specific tumor type and even varies greatly amongst individuals. Active targeting aims to incorporate a ligand complementary to a receptor that is known to be overexpressed, preferably exclusively expressed, on the surface of the target cancer cell. This allows the nanoparticle to interact with the cell, often entering by endocytosis and subsequently releasing the drug payload directly into the cytoplasm.

Nanoparticles also offer the possibility of simultaneous co-delivery of synergistic drugs in carefully balanced payloads, significantly improving the efficacy of each. Drug carriers constructed from lipids, polymers, silica, carbon, and metals have been investigated for this purpose, though no clinical trials have yet been initiated for these epigenetic drug-nanoparticle therapeutics.

Refined and specific epigenetic drugs will also allow fine control of the epigenome of animal models in research, allowing epigenetic diseases to be more closely modeled and drug leads better tested. The function of genes could also potentially be investigated in the future using specific epigenetic silencers or promoters, allowing researchers to easily turn genes “on” and “off” in a controlled and specific manner.

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