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Primer: epigenetics of autoimmunity

Abstract

Interactions between environmental and genetic factors are proposed to explain why autoimmunity afflicts certain individuals and not others. Genes and genetic loci predisposing to autoimmunity are being identified, but theories as to how the environment contributes to autoimmunity still rely largely on examples such as drug-induced systemic lupus erythematosus (SLE) and epidemiologic evidence of occupational exposure, without clear mechanistic explanations or identification of specific environmental agents. Eukaryotic gene expression requires not only transcription factor activation but also regional modification of chromatin structure into a transcriptionally permissive configuration through epigenetic mechanisms, including DNA methylation and histone modifications. The realization that epigenetic mechanisms can alter gene expression and, therefore, cellular function has led to new insights into how environmental agents might contribute to the development of diseases in genetically predisposed individuals. The observation that some SLE-inducing drugs, such as procainamide and hydralazine, affect T cell DNA methylation and thereby cellular function, and that identical changes in T cell DNA methylation and cellular function are found in patients with SLE, implicates epigenetic mechanisms in the pathogenesis of human SLE, and perhaps other autoimmune diseases. In this Review we discuss how epigenetic mechanisms affect gene expression, how environmental agents can affect epigenetic mechanisms, and how epigenetic changes in gene expression can contribute to autoimmunity. Similar mechanisms might also contribute to the pathogenesis of other poorly understood human diseases.

Key Points

  • DNA is packaged as chromatin in eukaryotic cells, and regional chromatin structure is determined by epigenetic mechanisms including DNA methylation and histone modifications

  • Gene expression requires two events: activation of transcription factors to permit binding to their recognition sequence, and localized remodeling of chromatin to permit assembly of the transcription initiation machinery

  • Environmental factors can modify chromatin structure, causing changes in gene expression

  • The systemic-lupus-erythematosus-inducing drugs procainamide and hydralazine inhibit T cell DNA methylation, which alters gene expression to cause autoreactivity and a lupus-like disease in animal models

  • T cells from patients with active systemic lupus erythematosus have identical changes in DNA methylation patterns, gene expression and function as T cells treated with DNA methylation inhibitors

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Figure 1: Relationship between DNA methylation, histone acetylation, and chromatin structure
Figure 2: Biochemistry of DNA methylation

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Acknowledgements

The author thanks Dr Amr Sawalha for assistance with illustrations, and Ms Cindy Bourke for her expert secretarial assistance. This work was supported by PHS grants and a Merit grant from the Veterans Administration.

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Richardson, B. Primer: epigenetics of autoimmunity. Nat Rev Rheumatol 3, 521–527 (2007). https://doi.org/10.1038/ncprheum0573

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