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Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland.
Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
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2019 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 49, no 5, p. 790-800Article in journal (Refereed) Published
Abstract [en]

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-alpha 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-alpha 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.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 49, no 5, p. 790-800
Keywords [en]
autoimmunity, chronic mucocutaneous candidiasis, epigenetics, STAT1 gain-of-function mutation, type I interferon
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-383152DOI: 10.1002/eji.201847955ISI: 000465252500014PubMedID: 30801692OAI: oai:DiVA.org:uu-383152DiVA, id: diva2:1315069
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved

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Syvänen, Ann-Christine

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