Oxidative stress and chromatin remodeling in chronic obstructive pulmonary disease and smoking-related diseases

Abstract

Significance: Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance.

Recent advances: Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress.

Critical issues: Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress.

Future directions: Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.

FIG. 1.

Differentially regulated chromatin modification genes and DNA methyltransferases are involved in cigarette smoke-mediated histone modifications. Unwinding and rewinding of DNA is regulated by epigenetic alterations, such as histone acetylation/deacetylation and histone methylation/demethylation. This includes histone acetylation by histone acetyltransferases (HATs), histone deacetylation by histone deacetylases (HDACs), histone methylation by SET domain proteins and histone methyltransferases (HMTs), histone demethylation by histone demethylases (HDMs), and DNA methylation by DNA methyltransferases (DNMTs), respectively. Cigarette smoke-mediated epigenetic changes and chromatin conformation changes can lead to alterations in DNA accessibility for transcription factors, coactivators, and polymerases, thereby, resulting in either transcriptional gene activation or gene repression of proinflammatory genes. Some examples of histone modification enzymes are given in parenthesis.

FIG. 2.

Role of redox kinase signaling in chromatin modifications. Cigarette smoke-derived oxidants/aldehydes activate several kinase signaling mechanisms, such as NIK, IKKα, MSK1, and PKCζ by redox modulation, and induce proinflammatory gene transcription via chromatin modifications. Upon activation of these kinases, NF-κB interacts with the master coactivator cAMP-response-element-binding protein (CBP/p300), and causes acetylation of specific lysine residues on core histones by displacing/decreasing histone deacetylases, leading to gene transcription. HATs, such as CBP/p300 and P/CAF, mediate histone acetylation (euchromatin) by loosening the nucleosomes, thereby, promoting access of cofactors and RNA polymerase II to mediate active gene expression. HDACs, such as SIRT1 and HDAC2, mediate deacetylation (heterochromatin) by tightly winding the nucleosomes, thereby, making the DNA inaccessible to transcription factors and other protein complexes, thus, resulting in gene repression.

FIG. 3.

Classes of histone deacetylases (HDACs/SIRTs). HDACs are classified into four distinct classes I to IV. Class I, class II (subclasses: IIa and IIb), and class IV HDACs are zinc-dependent enzymes, whereas class III HDACs that includes sirtuins (SIRTs: SIRT1–7) require nicotinamide adenine dinucleotide (NAD⁺) for catalytic activity.

FIG. 4.

Epigenetic regulation in cigarette smoke-mediated persistent DNA damage leading to chronic obstructive lung disease. Cigarette smoke-induced reduction in HDAC2/SIRT1 and DNA damage response proteins, such as Ku70 and Ku80, resulting in persistent DNA damage response. Cigarette smoke also alters the expression levels of chromatin modification enzymes, thus, affects epigenetic regulation of gene expression due to site-specific histone modification in histone H3 and H4. Persistent DNA damage further leads to stress-induced premature senescence/senescence-associated secretory phenotype, which subsequently causes premature aging of the lung in pathogenesis of chronic obstructive pulmonary disease (COPD) and smoking related disorders.

FIG. 5.

SIRT1 as master regulator of chronic inflammation, aging/senescence, and apoptosis/autopahgy. SIRT1 is a class III deacetylase that can deacetylate both histone and nonhistone proteins, including transcription factors, such as NF-κB, FOXO3, p53, p21, Ku70, and PGC1-α, thereby, regulating oxidative stress-induced chronic inflammation, cellular senescence, apoptosis, and autophagy, which play key roles in the pathogenesis of COPD. SIPS, stress-induced premature senescence.

FIG. 6.

Role of SIRT1, FOXO3, and NF-κB in oxidants/cigarette smoke-mediated lung inflammation. Regulation of SIRT1 activity by its substrate acetylated protein in presence of NAD⁺ will result in deacetylated protein, nicotinamide and acetyl ADP-ribose molecules (Left panel). SIRT1 activity and level are reduced by oxidative/carbonyl stress imposed by cigarette smoke leading to RelA/p65 and FOXO3 acetylation (Right panel). This results in downregulation of antioxidant genes, such as MnSOD and catalase, and NF-κB activation via its interaction with CBP favoring expression of proinflammatory and prosenescence genes.

FIG. 7.

Redox-mediated chromatin modifications in chronic inflammation and cellular senescence. Cigarette smoke-derived oxidants/carbonyls can activate various redox signaling cascades, thereby, leading to histone modifications on proinflammatory gene promoters. Histone modifications can cross talk with CpG methylation to activate or repress gene transcription. Modulation of various genes due to specific histone acetylation/methylation can result in inflammation and cellular senescence observed in chronic lung inflammatory diseases. Some of the known methylation and acetylation histone marks that either cause gene repression (H3K27me3 and H3K9me2/3) or gene activation (H3K9ac, H3K14ac, H3K4me3, H3K36me3, H3K79me3, H4K20me) are summarized.