Acetylation of histones and transcription-related factors. Sterner D E,Berger S L Microbiology and molecular biology reviews : MMBR The state of chromatin (the packaging of DNA in eukaryotes) has long been recognized to have major effects on levels of gene expression, and numerous chromatin-altering strategies-including ATP-dependent remodeling and histone modification-are employed in the cell to bring about transcriptional regulation. Of these, histone acetylation is one of the best characterized, as recent years have seen the identification and further study of many histone acetyltransferase (HAT) proteins and their associated complexes. Interestingly, most of these proteins were previously shown to have coactivator or other transcription-related functions. Confirmed and putative HAT proteins have been identified from various organisms from yeast to humans, and they include Gcn5-related N-acetyltransferase (GNAT) superfamily members Gcn5, PCAF, Elp3, Hpa2, and Hat1: MYST proteins Sas2, Sas3, Esa1, MOF, Tip60, MOZ, MORF, and HBO1; global coactivators p300 and CREB-binding protein; nuclear receptor coactivators SRC-1, ACTR, and TIF2; TATA-binding protein-associated factor TAF(II)250 and its homologs; and subunits of RNA polymerase III general factor TFIIIC. The acetylation and transcriptional functions of these HATs and the native complexes containing them (such as yeast SAGA, NuA4, and possibly analogous human complexes) are discussed. In addition, some of these HATs are also known to modify certain nonhistone transcription-related proteins, including high-mobility-group chromatin proteins, activators such as p53, coactivators, and general factors. Thus, we also detail these known factor acetyltransferase (FAT) substrates and the demonstrated or potential roles of their acetylation in transcriptional processes. 10.1128/MMBR.64.2.435-459.2000

Oxidative stress, transcription factors and chromatin remodelling in lung inflammation. Rahman Irfan Biochemical pharmacology Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders. Oxidants and inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha) activate transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to the expression of pro-inflammatory genes. The expression of many genes, including those encoding pro-inflammatory mediators involves the remodelling of the chromatin structure provided by histone proteins. Histone acetylation causes the unwinding of chromatin structure therefore allowing transcription factor access to promoter sites. Nuclear histone acetylation is a reversible process, and is regulated by a group of acetyltransferases (HATs) which promote acetylation, and deacetylases (HDACs) which promote deacetylation. In addition, several co-activators, transcription factors and nuclear proteins also have histone acetyltransferase activity. Both TNF-alpha and the oxidant, hydrogen peroxide (H2O2) alter histone acetylation/deacetylation, and the activation of NF-kappaB and AP-1, leading to the release of the pro-inflammatory cytokine interleukin-8 (IL-8) in human alveolar epithelial cells (A549). Pharmacological inhibition of HDAC leads to the increased HAT activity, AP-1 and NF-kappaB activation, and IL-8 release by H2O2 or TNF-alpha treatments. This suggests that the remodelling of chromatin by histone acetylation plays a role in the oxidant-mediated pro-inflammatory responses in the lungs. 10.1016/s0006-2952(02)01153-x

Epigenetics in asthma and other inflammatory lung diseases. Durham Andrew,Chou Pai-Chien,Kirkham Paul,Adcock Ian M Epigenomics Asthma is a chronic inflammatory disease of the airways. The causes of asthma and other inflammatory lung diseases are thought to be both environmental and heritable. Genetic studies do not adequately explain the heritability and susceptabilty to the disease, and recent evidence suggests that epigentic changes may underlie these processes. Epigenetics are heritable noncoding changes to DNA and can be influenced by environmental factors such as smoking and traffic pollution, which can cause genome-wide and gene-specific changes in DNA methylation. In addition, alterations in histone acetyltransferase/deacetylase activities can be observed in the cells of patients with lung diseases such as severe asthma and chronic obstructive pulmonary disease, and are often linked to smoking. Drugs such as glucocorticoids, which are used to control inflammation, are dependent on histone deacetylase activity, which may be important in patients with severe asthma and chronic obstructive pulmonary disease who do not respond well to glucocorticoid therapy. Future work targeting specific histone acetyltransferases/deacetylases or (de)methylases may prove to be effective future anti-inflammatory treatments for patients with treatment-unresponsive asthma. 10.2217/epi.10.27

Transcriptome remodeling in hypoxic inflammation. Safronova O,Morita I Journal of dental research Hypoxia is an integral component of the inflamed tissue microenvironment. Today, the influence of hypoxia on the natural evolution of inflammatory responses is widely accepted; however, many molecular and cellular mechanisms mediating this relationship remain to be clarified. Hypoxic stress affects several independent transcriptional regulators related to inflammation in which HIF-1 and NF-kappaB play central roles. Transcription factors interact with both HATs and HDACs, which are components of large multiprotein co-regulatory complexes. This review summarizes the current knowledge on hypoxia-responsive transcriptional pathways in inflammation and their importance in the etiology of chronic inflammatory diseases, with the primary focus on transcriptional co-regulators and histone modifications in defining gene-specific transcriptional responses in hypoxia, and on the recent progress in the understanding of hypoxia-mediated epigenetic reprogramming. Furthermore, this review discusses the molecular cross-talk between glucocorticoid anti-inflammatory pathways and hypoxia. 10.1177/0022034510366813

Histone acetylation and deacetylation: importance in inflammatory lung diseases. Barnes P J,Adcock I M,Ito K The European respiratory journal Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases. 10.1183/09031936.05.00117504