Severe Inflammatory Reactions in Mice Expressing a GFI1P2A Mutant Defective in Binding to the Histone Demethylase KDM1A (LSD1)

Abstract GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and deacetylases (HDACs). To study the consequences of disruption complex between histone-modifying enzymes, we have used knock-in mice harboring P2A mutation in coding region renders it unable to bind LSD1 associated enzymes HDACs. GFI1P2A die prematurely show increased numbers memory effector regulatory T cells spleen accompanied severe systemic inflammation high serum levels IL-6, TNF-α, IL-1β overexpression gene encoding cytokine oncostatin M (OSM). We identified lung alveolar macrophages, CD8 cell from thymic eosinophils, monocytes sources these cytokines mice. Chromatin immunoprecipitation showed GFI1/LSD1 occupy sites at Osm promoter an intragenic Tnfα mutant still remains bound even without LSD1. Methylation acetylation H3 were enriched mice, H3K27 being most significant. These data suggest modification facilitated critical control inflammatory pathways different types, including GFI1-associated can lead fatal consequences.