What is epigenetics?

Nearly every cell in a person's body has the same DNA sequence. Nevertheless, the activity of single genes differs significantly between different cell types and tissues. Epigenetics has been defined as hereditable changes in gene expression that are not attributable to the underlying genomic sequence [1]. It depends on three main and interrelated mechanisms: cytosine genomic DNA methylation, post-translational modification of histone proteins, and noncoding RNA modulation of gene expression [2] (click here for technical discussion). Epigenetic regulation is sensitive to both endogenous (e.g. hormonal) and exogenous (e.g. diet, exercise) factors, bridging the gap between genes and environment.

 

Epigenetics and autoimmune rheumatic diseases

Alterations of epigenetic markers have been described in association with the development and progression of common autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Osteoarthritis (OA), and Sjogren’s syndrome (SS). Most of published studies have focused on epigenetic analysis of immune cell types presumably implicated in autoimmune rheumatic diseases, revealing multiple layers of epigenetic dysregulation [2;3]. For instance, altered methylation and/or histone acetylation patterns have been described in fibroblast-like synoviocytes (RASFs) and leucocytes from RA patients, in chondrocytes from OA patients, in leucocytes from SLE patients, in T cells from SS patients, as well as in fibroblasts from SSc patients. Furthermore, studies investigating the effects of noncoding RNAs are gaining momentum, revealing that several miRNAs could play a significant role in most of these autoimmune conditions. Epigenetic changes seem to act as modifying factors of specific disease-related genes such as those regulating cell adhesion, transendothelial migration, extracellular matrix interactions and cytokine production. Polymyositis has not yet been investigated under this perspective. Nevertheless, considerable overlap exists between polymyositis and other autoimmune diseases in terms of pathogenesis and pathophysiology. Therefore, we can assume that epigenetic dysregulation could also contribute to this inflammatory myopathy.

 

Epigenetic-based therapies

Reversible nature of epigenetic alterations has encouraged the development of therapeutic strategies targeting the epigenome. [4;5]. Among them, histone deacetylase inhibitors (HDACIs) and DNA methyltransferases inhibitors (DNMTIs) are currently the most widely studied epigenetic therapeutics for autoimmune diseases. The use of HDACIs is currently being considered in the RA, SSc and SLE treatment. Indeed, several in vivo and in vitro studies have demonstrated their efficacy in attenuating inflammation and tissue damage. Furthermore, a clinical trial has been designed in order to evaluate safety and tolerability of an orally active HDACI (Givinostat) in patients with systemic juvenile idiopathic arthritis, showing a significant therapeutic benefit in terms of the arthritic component of the disease. With regard to DNMT inhibitors, -aza-2′-deoxycytidine has been shown to reverse the aberrant hypermethylation of genes involved in some autoimmune diseases such as SSc. Lastly, modulation of miRNA expression by using miRNA mimics or inhibitors has been investigated in several studies, showing a modifying effect on selected genes expression.

 

Conclusion and future perspectives

Genetic factors are not able to fully account for the risk of autoimmune rheumatic diseases. A growing series of evidences suggest a role of epigenetic alterations in their pathogenesis. The discovery of epigenetic markers shared by most of these disorders could offer the opportunity to develop targeted therapeutic strategies. Drugs such as HDACIs and DNMTIs have already been applied on animal models and clinical trials. Furthermore, microRNAs-targeting therapeutics are becoming a promising way for the modulation of several aspects of autoimmune diseases. It’s easy to argue that the rapid progress in the understanding of epigenetic regulation will significantly advance our knowledge of the processes and treatment of several diseases.

Article contributed by Dr. SARA NUOVO, MD

 

Footnotes:

[1] Egger G, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457-63. http://www.ncbi.nlm.nih.gov/pubmed/15164071

[2] Jeffries MA et al. Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve? Expert Rev Clin Immunol. 2015 Jan;11(1):45-58. Review. http://www.ncbi.nlm.nih.gov/pubmed/25534978

[3] Gay S et al. The emerging role of epigenetics in rheumatic diseases. Rheumatology (Oxford). 2014 Mar;53(3):406-14. Epub 2013 Sep 11. Review. http://www.ncbi.nlm.nih.gov/pubmed/24026248

[4] De Santis M et al. The therapeutic potential of epigenetics in autoimmune diseases. Clin Rev Allergy Immunol. 2012 Feb;42(1):92-101. Review. http://www.ncbi.nlm.nih.gov/pubmed/22161696

 

[5] Zhang Z et al. Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy. Autoimmun Rev. 2015 Oct;14(10):854-63. Epub 2015 May 27. Review. http://www.ncbi.nlm.nih.gov/pubmed/26026695