The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Abstract

Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD + , S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551-589.

Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay

“…It may be processed through the transulfation pathway to generate cysteine and GSH or be recycled to methionine and subsequently contribute to AdoMet pools through betaine homocysteine methyltransferase, which is expressed primarily in liver and kidney, or methionine synthase, which is broadly expressed. Studies to date indicate that the modulation of AdoMet pools have broad effects on epigenetic marks (37). Although H 2 O 2 has been shown to have a direct effect in modulating the activity of histone deacetylases (38), this is one of the first demonstrations of a direct role of reactive oxygen species in modulating the activity of DNA methyltransferase enzymes.…”

“…It is intriguing that a number of recently identified DNMT inhibitors are either quinones like nanaomycin (34) or dichlone (35) or are capable of generating H 2 O 2 (epigallocatechin-3-gallate (36)) These results, although raising questions regarding the utility of these types of inhibitors as potential therapeutics due to off target toxicity, do suggest a possible role for the cellular oxidation state in regulating methylation. The role of oxidative stress in modulating generation of glutathionine versus AdoMet is well known (37). Homocysteine, which is generated The cells were then harvested and genomic DNA was obtained.…”

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults

“…55 We also cannot establish whether the observed association with global DNA methylation is explained by an upstream factor (e.g., H 2 O 2 ), the GSH redox state itself or another redoxassociated event, e.g., alterations of the citric acid cycle and/or the NAD + /NADH ratio. 32 Finally, we were unable to adjust for PBMC cell type counts or distributions in our regression models.…”

“…30 Histone deacetylase (HDAC) inhibition has been shown experimentally to induce DNA hypomethylation, 31 and it has been hypothesized that HDAC activities might also be influenced directly by cellular redox. 32 In human neuroblastoma cells, exposure to H 2 O 2 induces global DNA hypomethylation, along with downregulation of HDAC3, DNMT1 and DNMT3a expression. 33 One potential mechanism of redox inhibition of HDACs might occur through alteration of cysteine residues: Reactive carbonyl species inactivate HDAC1 through covalent modification of conserved cysteine residues, 34 and exposure to ROS-producing compounds induces intramolecular disulfide bond formation in conserved cysteine residues in HDAC4.…”

Role of Mitochondria on the Neurological Effects of Cocaine

“…Mitochondrial DNA is subjected to epigenetic regulation (Shock, Thakkar, Peterson, Moran, & Taylor, 2011), and nuclear histone epigenetic modifications, chromatin remodeling, and nucleosome positioning depend on key substrates provided by mitochondria (Cyr & Domann, 2011). Mitochondrial energetics links the nuclear epigenome to calorie availability through intermediate metabolites, such as ATP, that can regulate the phosphorylation of cytosolic and nuclear signal transduction proteins; acetyl CoA, which regulates the acetylation of chromatin and signal transduction proteins; NAD 1 , that can modulate sirtuins to deacetylate proteins; and SAM, involved in histone and DNA methylation reactions (Wallace & Fan, 2010) (Fig.…”