A distal locus element mediates IFN-? priming of lipopolysaccharide-stimulated TNF gene expression.

ABSTRACT: Interferon ? (IFN-?) priming sensitizes monocytes and macrophages to lipopolysaccharide (LPS) stimulation, resulting in augmented expression of a set of genes including TNF. Here, we demonstrate that IFN-? priming of LPS-stimulated TNF transcription requires a distal TNF/LT locus element 8 kb upstream of the TNF transcription start site (hHS-8). IFN-? stimulation leads to increased DNase I accessibility of hHS-8 and its recruitment of interferon regulatory factor 1 (IRF1), and subsequent LPS stimulation enhances H3K27 acetylation and induces enhancer RNA synthesis at hHS-8. Ablation of IRF1 or targeting the hHS-8 IRF1 binding site in vivo with Cas9 linked to the KRAB repressive domain abolishes IFN-? priming, but does not affect LPS induction of the gene. Thus, IFN-? poises a distal enhancer in the TNF/LT locus by chromatin remodeling and IRF1 recruitment, which then drives enhanced TNF gene expression in response to a secondary toll-like receptor (TLR) stimulus.

SUBMITTER: Chow NA 

PROVIDER: S-EPMC4268019 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature