Histone acetylation and deacetylation: importance in inflammatory lung diseases

Abstract

Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kB. 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.

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…HDAC inhibitors (HDACIs) may sustain the activation of target genes via inhibition of HDACs [21,24]. More importantly, in cardiac cells, ADR leads to the degradation of p300, a major nuclear histone acetyltransferase, via a p38-mediated phosphorylation-dependent pathway [45,46]; in such a scenario, inhibition of HDACs may attenuate the decrease of acetylation levels due to the destruction of p300.…”

“…Acetylation homeostasis is a major epigenetic mechanism in cancer development and heart dysfunction [18][19][20], which is tightly regulated by the opposing histone acetyltransferases (HATs) and histone deacetylases (HDACs) [21,22]. Acetylation of histones opens chromatin structure for gene transcription; and acetylation also stabilizes and activates transcription factors for an increased activation of target genes [21].…”

“…Acetylation of histones opens chromatin structure for gene transcription; and acetylation also stabilizes and activates transcription factors for an increased activation of target genes [21]. Acetylation is negatively regulated by HDACs.…”

“…In mammals, there are four classes of HDACs (class I, IIa, IIb, III and IV) categorized based on homology to yeast HDACs [23]. Acetylation homeostasis can be easily modulated by the ever-growing members of HDAC inhibitors (HDACIs) [21,24], which currently categorized into six structurally distinct groups: short-chain fatty acids, hydroxamates, cyclic tetrapeptides, benzamides, electrophilic ketone, and miscellaneous [23,25].…”

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

“…Decreased histone deacetylase (HDAC) activity allows the acetylated chromatin to be unbound to histones. In turn, transcription factors can access the chromatin and the mRNA of distinct inflammatory cytokines and chemokines can be produced [7].…”