Epigenetic regulation of airway inflammation
Section snippets
Epigenetics
The term ‘epigenetics’ was introduced to describe all meiotically and mitotically heritable changes in phenotype or in gene expression states that are not coded in the DNA sequence itself [2••, 3•, 4]. Changes in DNA methylation and histone modification can selectively activate or inactivate genes that control cell growth, proliferation and apoptosis and determine when and where a gene is expressed during development [2••, 3•, 4]. Furthermore, with better methods for detection of these changes
Histone modifications
The expression and repression of genes is associated with alterations in chromatin structure by enzymatic modification of core histones [2••, 3•]. Specific residues (lysines, arginines and serines) within the N-terminal tails of core histones are capable of being post-translationally modified by acetylation, methylation, ubiquitination or phosphorylation, all of which have been implicated in the regulation of gene expression [2••, 3•].
Transcriptional co-activators such as CBP, SRC-1, TIF2,
Epigenetic regulation of tolerance
Repeated LPS exposure results in a dampened response and initially this was thought to occur with all genes [28•]. Recent results in murine macrophages indicate that these cells are tolerized to the pro-inflammatory effects of repeated LPS challenge but maintain sensitivity to anti-microbial actions thereby preventing systemic inflammation and septic shock [29••]. Tolerant (pro-inflammatory) and non-tolerant (anti-microbial) genes have distinct patterns of histone acetylation and methylation
Inhibition of histone deacetylases
Removal of acetyl tags by histone deacetylases (HDAC)s is generally associated with a lack of gene expression or gene silencing [36], and ample evidence exists that the HDAC inhibitor trichostatin A (TSA) enhances NF-κB-driven inflammatory gene transcription [19, 37••]. However, the idea that HDAC inhibitors (HDACi) merely increase histone acetylation across the genome thereby increasing gene expression cannot be correct since studies show that equal numbers of genes are suppressed as induced
Summary
Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by changes in DNA methylation and post-translational modifications of histones. These epigenetic changes are potentially reversible and raise the prospect of new treatment being produced for inflammatory airway diseases where conventional therapy is not effective. Altered patterns of methylation and acetylation have been reported in inflammatory diseases and
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Work in our Laboratory has been funded by the EU (Gabriel project), the Medical Research Council, the Wellcome Trust, AstraZeneca, GlaxoSmithKline, Mitsubishi Pharma (Japan), Novartis and Pfizer. Owing to constraints of space many excellent articles have not been cited for which we apologise.
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