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

  • Kaleviste, EppUniv Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia (författare)

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

  • Artikel/kapitelEngelska2019

Förlag, utgivningsår, omfång ...

  • WILEY,2019
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-383152
  • urn:nbn:se:uu:diva-383152urn
  • https://doi.org/10.1002/eji.201847955DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Saare, MarioUniv Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia (författare)
  • Leahy, Timothy RonanOur Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland (författare)
  • Bondet, VincentInst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France (författare)
  • Duffy, DarraghInst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France (författare)
  • Mogensen, Trine H.Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark (författare)
  • Jörgensen, Sofie E.Aarhus Univ, Dept Biomed, Aarhus, Denmark (författare)
  • Nurm, HelkeTallinn Childrens Hosp, Dept Emergency Care & Acute Infect, Tallinn, Estonia (författare)
  • Ip, WinnieGreat Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England (författare)
  • Davies, E. GrahamGreat Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England (författare)
  • Sauer, SaschaMax Planck Inst Mol Genet, Otto Warburg Lab, Berlin, Germany;Max Delbruck Ctr Mol Med, BIMSB, BIH, Lab Funct Genom Nutrigen & Syst Biol, Berlin, Germany (författare)
  • Syvänen, Ann-Christine,1950-Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)anncsyva (författare)
  • Milani, LiliUniv Tartu, Estonian Genome Ctr, Tartu, Estonia (författare)
  • Peterson, PärtUniv Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia (författare)
  • Kisand, KaiUniv Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia (författare)
  • Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, EstoniaOur Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:European Journal of Immunology: WILEY49:5, s. 790-8000014-29801521-4141

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