Reactive oxygen species, kinase signaling, and redox regulation of epigenetics

Abstract

Reactive oxygen species (ROS) cause alterations in the cellular redox status (GSH/GSSG ratio) and hence activate various kinase signaling pathways, redox sensitive transcription factors (NF-κB and AP-1), and chromatin modification enzymes leading to increased pro-inflammatory and immunological responses. Chromatin modification enzymes include histone acetyltransferases (HATs), histone and non-histone deacetylases (HDACs, sirtuins), histone methyltransferases (HMTs) and histone demethylases (HDMs). Activation of these enzymes results in transcriptional gene activation/repression. Histone methyltransferases are enzymes that dynamically cause histone mono-, di- or tri-methylation at lysine residues, which either result in gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Histone demethylases catalyze the removal of methyl groups from lysine or arginine residue of histones, hence regulating gene expression. Recent evidences have indicated that oxidative stress and environmental agents can alter nuclear histone acetylation/deacetylation/methylation, allowing access for transcription factor DNA binding and leading to enhanced pro-inflammatory gene expression. Cross-talks between histone modifications and DNA methylation also occur during inflammation. Understanding the mechanisms of ROS and redox epigenetic regulation via stress signaling kinases, redox sensitive transcription factors, the balance between histone acetylation/deacetylation and histone methylation/demethylation may lead to the development of novel therapies based on epigenetics against chronic inflammatory diseases, and cancer.