GSE120580
Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined
STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. STAT1 GOF mutations result in hyperphosphorylation and delayed dephosphorylation of STAT1. However, 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-a in STAT1 GOF patients were not persistently elevated. Nevertheless, the interferon signature was evident even in the patient with low or undetectable IFN-a levels. Chromatin immunoprecipitation (ChIP) experiments showed that the active chromatin mark H3K4me3, was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to normal cells. This suggests that GOF STAT1, while binding to chromatin, promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and interferon-related autoimmunity. We suggest that epigenetic rewiring may be responsible for treatment failure of JAK1/2 inhibitors in certain patients. We also found that after IL-21 stimulation the balance of p-STAT3/p-STAT1 was significantly impaired in patients, which could potentially be applied as a diagnostic test for STAT1 GOF. Overall design: ChIP-seq of 4 patient and 6 healthy control PBMC samples