HAT/HDAC: The epigenetic regulators of inflammatory gene expression (Review)

Abstract

Inflammation is a condition through which the body responds to infection or tissue injury. It is typically characterized by the expression of a plethora of genes involved in inflammation, that are regulated by transcription factors, transcriptional co-regulators, and chromatin remodeling events. Differential mitotically heritable patterns of gene expression without changes in the DNA sequence are essentially controlled by epigenetic regulation. Epigenetic mechanisms, such as histone modifications and DNA methylation have a profound effect on inflammatory gene transcription. Histone protein modifications, which include acetylation and the ubiquitination of lysine residues, the methylation of lysine and arginine, and the phosphorylation of serine have been found to modulate chromatin dynamics, thus altering the levels of gene expression. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate the addition and removal of acetyl groups from lysine residues on histones respectively. Nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-6 are the pro-inflammatory genes known to promote inflammatory responses in cells. By contrast, 15-lipoxygenase-1 (15-LOX-1) and monoamine oxidase-A (MAO-A) are the genes that can act against inflammation in certain specific conditions. 15-LOX-1, a lipid peroxidative enzyme, is associated with the development of inflammatory disorders, such as atherosclerosis, rheumatoid arthritis, asthma and renal injury. MAO-A catalyzes degradation of biogenic amines and has been reported to cause oxidative stress, atherosclerosis and neuroinflammation. 15-LOX-1 has been shown to be co-expressed along with MAO-A, in both primary human monocytes and A549 lung carcinoma cells upon treatment with Th2 cytokines, such as IL-4 and IL-13. The present review aimed to discuss the HAT-and HDAC-mediated epigenetic machinery which governs the expression of pro-inflammatory genes, such as IL-6, TNF-α, etc., as well as the expression of anti-inflammatory genes, such as 15-LOX-1 and MAO-A, responsible for modulating the process of inflammation. On the whole, the present review aims to provide deeper insight into the underlying molecular mechanisms involved in the epigenetic regulation of inflammation, which may have novel implications in designing small molecule inhibitors that target the epigenetic machinery for the effective treatment of a variety of inflammation-related diseases. Contents1. Introduction 2. Role of HAT and HDAC in regulating pro-inflammatory gene expression 3. Role of HAT and HDAC in regulating anti-inflammatory gene expression 4. Conclusion and future perspectives

Development of a novel class of CBP/EP300 bromodomain inhibitors which block TNF-α induced NFκB signaling

“…Small molecule inhibitors of TNF-α signaling that directly prevent the interactions between TNF-α and TNFR1/2 have been pursued, but none of them have reached the clinic up to date and substantial efforts continue to be deployed in this area 49 . Epigenetics provides an alternative approach to reduce TNF-α activity 11 . CBP/EP300 are two highly homologous bromodomain proteins, known to regulate inflammatory transcription factors.…”

“…Interestingly, several approaches are now being investigated to block TNF-α using small molecules, none of which have reached the clinic to date 9,10 . However, epigenetics -known to regulate the signaling pathways downstream of TNF-α 11 -offer an alternative approach to inhibiting TNF-α beyond directly blocking the interaction between TNF-α and TNFR1/2.…”

Inhibiting SIRT-2 by AK-7 restrains airway inflammation and oxidative damage promoting lung resurgence through NF-kB and MAP kinase signaling pathway

“…Studies prove that the absence of Nrf-2 can increase NF-κB activity and lead to increased cytokine production, which is related to increased oxidative stress. However, SIRT-2 deacetylates p65 in the cytoplasm, controlling the expression of particular NF-kB-dependent genes ( 63 ). Consistent with the abovementioned findings, our results also showed a significant decrease in Nrf-2 and increase in NF-κB expression in the COPD group, suggesting that inflammation is mediated through the increased expression of NF-κB.…”