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The ascent of acetylation in the epigenetics of rheumatoid arthritis

Nature Reviews Rheumatology volume 9, pages 311–318 (2013)Cite this article

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Abstract

Genome-wide association studies have shown that genetic polymorphisms make a substantial but incomplete contribution to the risk of developing rheumatoid arthritis (RA). Efforts to understand the nongenetic contributions to RA disease susceptibility have recently focused on the study of epigenetic mechanisms, namely modifications of DNA and histones, which are subject to environmental influences and regulate gene expression. A surprising theme emerging from studies of the enzymes responsible for these epigenetic modifications, particularly histone deacetylases, is that they regulate inflammatory activation of cell populations relevant to RA through independent, direct, and dynamic interactions with nonhistone proteins. Herein, we highlight studies, the findings of which collectively suggest that revisiting the original definition of epigenetics, conceived some 70 years ago, might advance our interpretation of DNA and histone modifications with regard to gene expression and clinical outcome in RA. Such an approach could also facilitate the development of strategies to target these epigenetic modifications in the clinic.

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Figure 1: The 'working' definition of epigenetic regulation of gene expression.
Figure 2: Compounds targeting the epigenetic regulatory machinery and their effects on cell populations relevant to RA.
Figure 3: Integration of histone modifications, histone-modifying enzymes and signal transduction to regulate gene expression and phenotype in RA.
Figure 4: Applying the epigenetics of Waddington6 to studies in RA.

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Author information

Authors and Affiliations

  1. Department of Experimental Immunology, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands

    Aleksander M. Grabiec & Kris A. Reedquist

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  1. Aleksander M. Grabiec
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  2. Kris A. Reedquist
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Contributions

A. M. Grabiec and K. A. Reedquist contributed equally to all stages of the preparation of this manuscript.

Corresponding author

Correspondence to Kris A. Reedquist.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Postulated mechanism of HDAC inhibitor action in animal models of arthritis (DOC 54 kb)

Supplementary Table 2

Biological roles of HDAC isoforms in cells relevant to RA pathology (DOC 58 kb)

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Grabiec, A., Reedquist, K. The ascent of acetylation in the epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9, 311–318 (2013). https://doi.org/10.1038/nrrheum.2013.17

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