The role of epigenomics in personalized medicine

Abstract

Introduction Epigenetics is the study of reversible modifications to chromatin and their extensive and profound effects on gene regulation. To date, the role of epigenetics in personalized medicine has been under-explored. Therefore, this review aims to highlight the vast potential that epigenetics holds. Areas covered We first review the cell-specific nature of epigenetic states and how these can vary with developmental stage and in response to environmental factors. We then summarize epigenetic biomarkers of disease, with a focus on diagnostic tests, followed by a detailed description of current and pipeline drugs with epigenetic modes of action. Finally, we discuss epigenetic biomarkers of drug response. Expert commentary Epigenetic variation can yield information on cellular states and developmental histories in ways that genotype information cannot. Furthermore, in contrast to fixed genome sequence, epigenetic patterns are plastic, so correcting aberrant, disease-causing epigenetic marks holds considerable therapeutic promise. While just six epigenetic drugs are currently approved for use in the United States, a larger number is being developed. However, a drawback to current therapeutics is their non-specific effects. Development of locus-specific epigenetic modifiers, used in conjunction with epigenetic biomarkers of response, will enable truly precision interventions.

HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants

“…In general, we now appreciate that HDACi mediate acetylation/deacetylation balance of both histones (regulating transcriptional events) as well numerous non-histone proteins-highlighted by the dynamic acetylome that includes proteostasis [1, [25][26][27][28][29][30][31] components regulating the central heat shock response (HSR) [32] and unfolded protein response (UPR) [33,34], programs responsible for recovery from protein folding stress such as the maladaptive stress caused by CFTR misfolded variants [24,[35][36][37][38][39][40][41]. By globally adjusting the cellular environment in as yet to defined but integrated ways, HDACi could be adjusting interacting pathways that restore maladaptive states responding to a variant challenge by creating a more globally permissive folding environment-in essence, leveling the playing field.…”

“…Transferases (HATs), as well as by other factors including Histone Methyl Transferases (HMTs), Histone DeMethylases (HDMs), and Bromo-Domain (BD) proteins-together comprising the 'reader, writer, eraser' cohort that differentially manage the genome for each individual [20][21][22][23][24]. HATs/HDACs mediate the acetylation balance of histones, which manage the open and closed chromatin states to provide access to transcription factors.…”

“…We now appreciate the importance of epigenetic modifications, such as methylation and acetylation, as key features impacting genetic diversity during development and aging, and in response to environmental changes. Epigenomic changes are regulated by Histone Deacetylases (HDACs) and Histone Acetyl Transferases (HATs), as well as by other factors including Histone Methyl Transferases (HMTs), Histone DeMethylases (HDMs), and Bromo-Domain (BD) proteins-together comprising the 'reader, writer, eraser' cohort that differentially manage the genome and inevitably, the proteome, for each individual [20][21][22][23][24]. HATs/HDACs mediate the acetylation balance of histones, which manage the open and closed chromatin states to provide access to transcription factors.…”

“…How HDAC-regulated epigenomic programs translate genetic diversity in the genome into a functional proteome to contribute differentially to health and disease over the lifespan of each CF individual remains a challenge to understand. There is now considerable interest in the use of HDACi to improve the management of numerous protein folding diseases including CF, Niemann-Pick C1 (NPC1) [43][44][45][46], Alpha-1-AntiTrypsin Deficiency (AATD) [47][48][49], as well as lysosomal disorders [24,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Moreover, there is an ever-growing body of evidence that HDACi could play a crucial therapeutic role in somatic/complex disease including lung fibrosis/Chronic Obstructive Pulmonary Disease (COPD) [66], arthritis, hypertension, septic shock, and neurodegenerative disease including Alzheimer's, Huntington, and Parkinson's [67][68][69].…”

“…HDACs, grouped into 4 classes (I-IV) with a wide range of substrate specificities based on domain structures flanking the highly conserved catalytic site found in each isoform that controls their target specificity, such as found in the Zn 2+ -dependent class I & II enzymes. The conserved design of catalytic pocket of class I and II enzymes has made it challenging to generate isoform specific inhibitors, although progress is now being made for a select group of HDACs [24,60,61,[75][76][77][78][79][80], including HDAC7 [81,82]. HDACi can have both positive and negative effects on gene expression and protein function depending on the Lys/Arg residues affected by the targeted HDAC and the role of these residues in protein function.…”