Epigenetic regulation of airway inflammation

doi:10.1016/j.coi.2007.07.016

Current Opinion in Immunology

Volume 19, Issue 6, December 2007, Pages 694-700

https://doi.org/10.1016/j.coi.2007.07.016 Get rights and content

Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by epigenetic changes. Transcriptional co-activators possess intrinsic histone acetyltransferase (HAT) activity, and histone acetylation plays a major role in inflammatory gene expression. Other marks such as histone methylation are also associated with gene induction and gene repression. Recent evidence implicates histone acetylation and methylation as being crucial for the development of tolerance in macrophages and CpG methylation for T regulatory cell development and function. The expression of the enzymes that lay down or remove these epigenetic marks have not been well studied in human airways disease, but reduced HDAC2 expression and activity is reported in lung macrophages, biopsies and blood cells from patients with COPD, severe asthma and smoking asthma. In vitro, inhibitors of histone deacetylases (HDAC) often lead to a further induction of inflammatory gene expression. This is not always the case, however, as HATs and HDACs also target non-histone proteins particularly transcription factors to alter their activity. Furthermore, trichostatin A, an HDAC inhibitor, can reduce inflammation in a murine model of allergic asthma. This effect of HDAC inhibitors may be due to their effects on cell death acting through acetylation of non-histone proteins. The role of epigenetic modifications in inflammatory gene expression and in the control of cell function in the airways is becoming clearer. Targeting specific enzymes involved in this process may lead to new therapeutic agents, in particular, in situations where current anti-inflammatory therapies are currently suboptimal.

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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Epigenetic regulation of airway inflammation

Section snippets

Epigenetics

Histone modifications

Epigenetic regulation of tolerance

Inhibition of histone deacetylases

Summary

References and recommended reading

Acknowledgements

Cell

J Intern Med

FASEB J

J Biol Chem

Eur Respir J

Genetics and epigenetics—nature's pen-and-pencil set

N Engl J Med

Histone acetyltransferase complexes: one size doesn’t fit all

Nat Rev Mol Cell Biol

Epigenetic regulation by histone methylation and histone variants

Mol Endocrinol

DNA methylation mapping by tag-modified bisulfite genomic sequencing

Anal Biochem

Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancers

Cancer Res

DNA methylation and human disease

Nat Rev Genet

Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription

Nat Genet

CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation

J Exp Med

Epigenetic control of the foxp3 locus in regulatory T cells

PLoS Biol

Identification of a macrophage-specific chromatin signature in the IL-10 locus

J Immunol

DNA methylation changes at human Th2 cytokine genes coincide with DNase I hypersensitive site formation during CD4(+) T cell differentiation

J Immunol

Epigenetic regulation of human alpha1d-adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation

FASEB J

Chromatin-dependent cooperativity between site-specific transcription factors in vivo

J Biol Chem

Nuclear receptors and chromatin remodeling machinery

Mol Cell Endocrinol

Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response

Genes Dev

NF-κB and Activator Protein 1 response elements and the role of histone modifications in IL-1β-induced TGF-β1 gene transcription

J Immunol

Epigenetics and airways disease

Respir Res

β2-Adrenoceptor agonists, like glucocorticoids, repress eotaxin gene transcription by selective inhibition of histone H4 acetylation

J Immunol

β₂-Adrenoceptor agonists, like glucocorticoids, repress eotaxin gene transcription by selective inhibition of histone H4 acetylation