Epigenomic Networking in Drug Development: From Pathogenic Mechanisms to Pharmacogenomics

Abstract

Different epigenetic alterations (DNA methylation, histone modifications, chromatin remodeling, noncoding RNA dysregulation) are associated with the phenotypic expression of complex disorders in which genomic, epigenomic, proteomic, and metabolomic changes, in conjunction with environmental factors, are involved. As epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions, a series of epigenetic drugs have been developed, including DNA methyltransferase inhibitors (nucleoside analogs, small molecules, bioproducts, antisense oligonucleotides, miRNAs), histone deacetylase inhibitors (short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, ketones, sirtuin inhibitors, sirtuin activators), histone acetyltransferase modulators, histone methyltransferase inhibitors, histone demethylase inhibitors, and noncoding RNAs (miRNAs), with potential effects against myelodysplastic syndromes, different types of cancer, and neurodegenerative disorders. Pharmacogenetic and pharmacoepigenetic studies are required for the proper evaluation of efficacy and safety issues in clinical trials with epigenetic drugs.

Epigenetics of Brain Disorders: The Paradigm of Alzheimer ’s Disease

“…Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in multiple modalities of brain disorders [9,[15][16][17]. Altered DNA methylation patterns may account for phenotypic changes associated with human aging.…”

Neuroepigenetics: Prospects and Illusions

“…Proteomic biomarkers and epigenomic signatures may help in the prediction, early diagnosis, and prognosis of CNS disorders. Additionally, some epigenetic modifications are conceptually reversible and can potentially be targeted by pharmacological and dietary interventions [10][11][12]. Of paramount importance is the fact that epigenetic changes in genes involved in pharmacogenomics can also influence drug efficacy and safety and drug resistance in brain disorders and cancer [1].…”

“…Epigenetic drugs are becoming a fashion [14][15][16] and some of them have been approved by the FDA in recent years for the treatment of cancer [17]. However, most epigenetic drugs are pleiotropic and are not devoid of toxicity and biodynamic complications (e.g.…”

“…However, most epigenetic drugs are pleiotropic and are not devoid of toxicity and biodynamic complications (e.g. brain penetration) [14].…”

“…In practice, the expression of these genes is potentially modifiable (transcriptionally and/or post-transcriptionally) by epigenetic mechanisms which may alter (i) pathogenic events, (ii) receptordrug interactions, (iii) drug metabolism (phase I and II enzymatic reactions), (iv) drug transport (influx-efflux across membranes and cellular barriers), and (v) pleiotropic events leading to unexpected therapeutic outcomes. The understanding of these mechanisms is the main focus of pharmacoepigenomics in order to optimize therapeutics and advance towards a personalized medicine [2,14,18].…”