Medical Crash Review Explain the Role of Epigenetics in Pharmacologic Action

April 16, 2022 Post a Comment

Research efforts aimed at improving our understanding of the role epigenetic factors play in disease have increased significantly in recent years, with epigenetic dysregulation linked to numerous diseases including; several cancers, autoimmune disorders and neurological disorders.¹

This association has ignited interest in developing ways to therapeutically target epigenetic regulation – particularly as many epigenetic modifications are reversible. This commodity aims to highlight the fundamental types of epigenetic modification, summarize electric current and emerging drug discovery efforts to target epigenetic dysregulation and will discuss some of the benefits and challenges of epigenetic therapeutics.

What is Epigenetics?

Epigenetics is the study of modifications to Deoxyribonucleic acid that change the fashion genes are expressed. It does not modify the underlying genetic code of an individual. Epigenetic modifications touch when genes are turned on and off.

Dr Manel Esteller, Director of the Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL) elaborates: "Epigenetics is the inheritance of factor activity that does non depend on the naked Deoxyribonucleic acid sequence. Thus, are all those chemical modifications in Dna, RNA and proteins that confer the differential activity and identity to the cells and tissues of our torso that have identical genomes. The well-nigh studied epigenetic marks are Dna methylation and histone modification."

Types of Epigenetic Modification

Epigenetic Mechanism	Clarification
Deoxyribonucleic acid Methylation	DNA methyltransferases (DNMTs) add together a methyl group (CH₃) to Dna, this addition acts as a 'tag' which can lead to either the activation or (more unremarkably) the repression of gene expression.² (Figure 1) One of the most well-characterized Deoxyribonucleic acid methylations is the add-on of the methyl grouping at the v-position of the cytosine nucleotide band which results in the formation of v-methyl-cytosine (five-mC).³
Histone Modification	Epigenetic factors bind to histone 'tails' which changes the extent to which Deoxyribonucleic acid is wrapped around each histone. This alters the accessibility of genes, DNA that would usually be 'hidden' may become 'visible' and consequently genes inside that section of Deoxyribonucleic acid can be transcribed and expressed.ⁱⁱ(Effigy one) The most well-characterized histone modifications are the methylation (by histone methyltransferases) and acetylation (by acetylases) of H3 and H4.³
Genomic Imprinting	Genomic imprinting results in genes being expressed in a parent-of-origin specific manner. Some genes are expressed from the maternally inherited allele, whereas others are expressed from the paternally inherited allele.⁴

Figure i. Visualization of the ii main types of epigenetic modification; DNA methylation, and histone modification. Credit: National Institutes of Health .

"There are at least two ways that epigenetics can be useful for drug discovery. Showtime, the enzymes that are responsible for altering the epigenetic code can be targeted. This arroyo would "remodel" the chromatin and affect global factor regulation on a large calibration," says Gary South. Firestein, MD, Associate Vice Chancellor and Dean of Translational Medicine at UC San Diego Health.

"Alternatively, abnormal epigenetic marks could exist used to ascertain individual genes that are responsible for disease. Instead of targeting the epigenetics, the gene that is abnormally regulated could be the focus of drug discovery efforts."

Identifying Drug Targets Using Epigenetics

"Most human being disorders evidence a loss or change in jail cell identity. It can exist a degeneration (Alzheimer's), an young state (neurodevelopmental disorders) or a transformation (cancer). Thus, drugs that target the proteins involved in writing, reading or erasing these epigenetic marks are attractive targets for drug development. In the field of oncology, DNA demethylating agents and histone deacetylase inhibitors are approved for clinical use in subtypes of leukemias and lymphomas," explains Esteller.

Rheumatoid Arthritis & Huntington'due south Disease Connectedness Discovered Using Epigenetics

Earlier this yr researchers from the University of California San Diego Schoolhouse of Medicine and the Icahn School of Medicine at Mount Sinai reported key study findings unveiling the comprehensive epigenomic characterization of fibroblast-like synoviocytes (FLS) – a central cell type implicated in rheumatoid arthritis (RA). By 'decoding' RA's epigenetic mural the team identified overlap between the cause of RA and Huntington's disease.

"Using a novel algorithm to integrate the massive amount of data generated allowed us to determine which genes and pathways are abnormally regulated in RA. Although we constitute many genes related to amnesty, which was not a surprise, the power of the method, was its ability to identify the unexpected pathways that could play a role. To our surprise, Huntington's disease related genes were consistently the highest priority genes that distinguished RA. This was unanticipated and is part of the excitement of using unbiased methods." explains Gary Southward. Firestein, Medico, lead author of the written report.

They were able to validate the role of a cardinal protein involved in the "Huntington's Disease Signaling" pathway indicating that the written report method could be used as a means for identifying new therapeutic targets.

Firestein comments on the potential of their approach as a means for helping patients with other immune-mediated diseases: "By studying the genes that are abnormally regulated, we can find novel targets that could not have been gleaned from reading the literature. Every bit nosotros mine the data, we await to find many genes that could be used for drug discovery. The platform that nosotros developed is "disease-doubter"; in other words, we could collect the same type of data for other diseases and identify expected and unexpected pathways that volition point to new ways to develop drugs. Nosotros are already beginning to do this for other allowed-mediated diseases."

Epigenetics in Cancer

The first human disease to be linked to epigenetics was cancer – dorsum in 1983.^5,6 Interest in cancer epigenetics has since connected to increase, with specific attending being given to the broadening understanding of different epigenetic mechanisms, including hypo- and hyper-methylation, loss of imprinting, and chromatin modification.⁵
Esteller and his team currently work on the interactions betwixt epigenetic modifications and not-coding RNAs and focus their efforts on the development of novel epigenetic drugs: "Nosotros are always looking for new epigenetic drugs that at the preclinical stage might be beneficial to treat human pathologies. In the past nosotros were involved in the initial stages of implementation of the DNA demethylating agents and the histone deacetylase inhibitors and studied new compounds that act as inhibitors of sirtuins (a special blazon of histone deacetylase), histone kinases such equally haspin, inhibitors of histone methyltransferases or blockers of histone acetylation reading (bromodomain inhibitors)."

Epigenetic Drug Confronting Mantle Cell Lymphoma

Esteller's team recently produced a first-in-class inhibitor of the histone deacetylase half dozen (HDAC6) that among hundreds of different types of cancer cells showed a higher activity for a subtype of lymphoma called drape cell lymphoma (MCL). Their findings were published in the journal Haematologica.

The researchers demonstrated the efficacy of the compound in cultured cells, murine studies and cells extracted from MCL patients. "It works in these models by inducing cell death (apoptosis)," says Esteller.

Esteller highlights some of the advantages of using epigenetic drugs for the handling of cancer: "These drugs have a lower toxicity, they are not very expensive, and they accept the chapters to induce differentiation of transformed cancer cells. In addition, they tin be combined with other types of drugs and take the potential to enhance the effect of immunotherapy."

However, information technology should be noted that at that place is evidence of discrepancy in the efficacy of epigenetic cancer drugs. "Solid tumors such as those associated with colorectal, lung and pancreatic cancer seem somewhat resistant to these drugs, epigenetic drugs are more constructive against hematological malignancies and sarcomas." cautions Esteller.

Targeting Epigenetic Mechanisms: Considerations & Challenges

Due to the limited number of enzymes involved in Deoxyribonucleic acid methylation, there has been hesitancy to consider them as suitable therapeutic targets – as inhibiting these enzymes would likely pb to broad and potentially serious adverse toxicological effects.⁷ Firestein cautions: "If we focused more than on remodeling the chromatin by targeting enzymes that are responsible for creating the epigenetic marks, ane business organization could be potential side furnishings. These inhibitors could have an upshot on illness-related genes too as genes involved with normal cell function. The rest between prophylactic and efficacy could be a very fine line."

An alternative selection may be to target the procedure and regulation of histone modification – as it requires a vast number of proteins with specialized roles – this individual functionality aids ane's power to selectively target a specific protein, thereby limiting chances of toxicity.⁷

However, identifying the right target may not exist like shooting fish in a barrel, explains Firestein: "One of the key challenges is wading through the multitude of potential targets and prioritizing them. In that location is no shortage of abnormally regulated genes, and it would be very difficult to test them all."

"However, a main reward is the unbiased nature of the inquiry and the ability to find the unexpected…"

References

1. Moosavi A, Ardekani AM. Part of Epigenetics in Biology and Man Diseases. Iran Biomed J. 2016;20(5):246–58.
2. Bonetta 50. Epigenomics: The new tool in studying complex diseases. Nature Education. 2008;i(1):178.
3. Academy of Leicester. Introduction to epigenetics. Retrieved from: https://www2.le.ac.uk/projects/vgec/highereducation/epigenetics_ethics/Introduction#types-of-epigenetic-modification
4. Ferguson-Smith AC. Genomic imprinting: the emergence of an epigenetic prototype. Nature Reviews Genetics. 2011;12:565–75.
5. Feinberg AP, Tycko B. The history of cancer epigenetics. Nature Reviews Cancer. 2004;4:143–53.
6. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human being cancers from their normal counterparts. Nature. 1983;301:89–92.
7. Tough DF, et al. Epigenetic drug discovery: breaking through the immune barrier.Nature Reviews Drug Discovery. 2016;15:835–53.