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Sökning: onr:"swepub:oai:DiVA.org:uu-383152" > Interferon signatur...

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

Kaleviste, Epp, (författare)
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia
Saare, Mario, (författare)
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia
Leahy, Timothy Ronan, (författare)
Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland
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Bondet, Vincent, (författare)
Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France
Duffy, Darragh, (författare)
Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France
Mogensen, Trine H., (författare)
Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark
Jörgensen, Sofie E., (författare)
Aarhus Univ, Dept Biomed, Aarhus, Denmark
Nurm, Helke, (författare)
Tallinn Childrens Hosp, Dept Emergency Care & Acute Infect, Tallinn, Estonia
Ip, Winnie, (författare)
Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England
Davies, E. Graham, (författare)
Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England
Sauer, Sascha, (författare)
Max Planck Inst Mol Genet, Otto Warburg Lab, Berlin, Germany;Max Delbruck Ctr Mol Med, BIMSB, BIH, Lab Funct Genom Nutrigen & Syst Biol, Berlin, Germany
Syvänen, Ann-Christine, 1950- (författare)
Uppsala universitet, Molekylär medicin, Uppsala universitet, Science for Life Laboratory, SciLifeLab
Milani, Lili, (författare)
Univ Tartu, Estonian Genome Ctr, Tartu, Estonia
Peterson, Pärt, (författare)
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia
Kisand, Kai, (författare)
Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia
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Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet. Medicinska fakulteten. Institutionen för medicinska vetenskaper. Molekylär medicin. (creator_code:org_t)
Uppsala universitet Science for Life Laboratory, SciLifeLab. (creator_code:org_t)
2019
Engelska.
Ingår i: European Journal of Immunology. - WILEY. - 0014-2980 .- 1521-4141. ; 49:5, s. 790-800
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

autoimmunity
chronic mucocutaneous candidiasis
epigenetics
STAT1 gain-of-function mutation
type I interferon

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