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Interferon target-gene expression and epigenomic signatures in health and disease

Abstract

Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak–STAT signaling pathway and induce overlapping patterns of expression, called ‘interferon signatures’, of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an ‘interferon epigenomic signature’ by activating latent enhancers and ‘bookmarking’ chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.

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Fig. 1: IFN-induced signaling and overlapping patterns of gene expression.
Fig. 2: Nucleic acid sensors and downstream signaling pathways induce type I IFN production.
Fig. 3: Epigenomic regulation links type I IFN signaling to induction of inflammatory non-ISGs.

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Acknowledgements

This work was supported by grants from the NIH (to F.J.B. and L.B.I.) and from the Scleroderma Research Foundation (to F.J.B.).

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Correspondence to Lionel B. Ivashkiv.

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F.J.B. has been acting as a consultant for Astra Zeneca, Janssen and EMD Serono but has no other conflicts. M.K.C. has served as a consultant for Astra Zeneca, Bristol-Myers Squibb, Janssen, Lilly and Novartis. L.B.I. serves as a consultant for Lilly but does not accept any personal compensation.

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Barrat, F.J., Crow, M.K. & Ivashkiv, L.B. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol 20, 1574–1583 (2019). https://doi.org/10.1038/s41590-019-0466-2

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