Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD - PubMed (original) (raw)

Review

Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD

Saravanan Rajendrasozhan et al. COPD. 2009 Aug.

Abstract

Chromatin modifications and epigenetic regulation are critical for sustained and abnormal inflammatory response seen in lungs of patients with chronic obstructive pulmonary disease (COPD) because the activities of enzymes that regulate these epigenetic modifications are altered in response to cigarette smoke. Cigarette smoke induces chromatin modifications and epigenetic changes by causing post-translational modifications of histone acetyltransferases, and histone/non-histone deacetylases (HDACs), such as HDAC2 and sirtuin 1 (SIRT1), which leads to chromatin remodeling. In this review, we discussed the current knowledge on cigarette smoke/oxidants-induced post-translational modifications of deacetylases (HDAC2 and SIRT1), disruption of HDAC2/SIRT1-RelA/p65 corepressor complex associated with acetylation of RelA/p65, and chromatin modifications (histone H3 phospho-acetylation) leading to sustained pro-inflammatory gene transcription. Knowledge on molecular mechanisms of epigenetic changes in abnormal lung inflammation will help in understanding the pathophysiology of COPD which may lead to the development of novel epigenetic therapies in the near future.

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Figures

Figure 1. Regulation of NF-κB-dependent gene expression by histone acetyltransferases (HATs) and histone deacetylases (HDACs)

DNA is coiled around the histone proteins and form chromatin structure. Acetylation of histones leads to opening of the chromatin and increasing the accessibility of transcription factors, such as NF-κB. HATs acetylate histones and RelA/p65 (subunit of NF-κB) which facilitate the binding RelA/p65-p50 heterodimer onto the pro-inflammatory gene promoters and thereby increasing gene transcription. Deacetylation results in DNA rewinding around histone proteins, and decreasing gene transcription. Thus, HDACs are involved in the maintenance of histone acetylation and deacetylation balance thereby control the transcription of gene. In response to cigarette smoke exposure, deacetylases (especially HDAC2 and SIRT1) are post-translationally modified by phosphorylation, carbonylation, aldehyde adducts formation and/or nitration/nitrosylation leading to increased ubiquitination and subsequent degradation of deacetylases. Decrease in deacetylases results in increased histone acetylation/deacetylation ratio resulting in increased acetylation of histones (chromatin remodeling) and NF-κB subunits leading to increased transcription of pro-inflammatory mediators. Dotted lines indicate less function (less phosphorylation and acetylation) whereas solid lines indicate increased function (more phosphorylation and acetylation). HAT: Histone acetyltransferase; HDAC: Histone deacetylase; P: Phosphorylation; Ac: Acetylation; 4-HNE: 4-hydroxy-2-nonenal; NO2: Nitrogen dioxide.

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Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD - PubMed (original) (raw)