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Article Dans Une Revue European Journal of Immunology Année : 2019

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Résumé

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

Dates et versions

pasteur-02119249 , version 1 (03-05-2019)

Identifiants

Citer

Epp Kaleviste, Mario Saare, Timothy Ronan Leahy, Vincent Bondet, Darragh Duffy, et al.. Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined. European Journal of Immunology, 2019, 49 (5), pp.790-800. ⟨10.1002/eji.201847955⟩. ⟨pasteur-02119249⟩

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