Abstract
The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB-binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class; however, it effects repression by targeting distinct temporal events and components of transcriptional machinery.
Highlights
Inflammation is an innate immune response to tissue injury or infection
At FDR < 0.1 we found that, compared to vehicle-treated bone-marrow-derived macrophages (BMDM), 597 genes were induced by LPS >1.5 fold
LPS + Dex unique peaks are enriched for NF-kB-binding sites as indicated by MEME-ChIP analysis as in B. (D) Genomic location of p65 and glucocorticoid receptor (GR) binding sites relative to known genomic features is determined by ChIPpeakAnno (Bioconductor) (Zhu et al, 2010). (E) The distribution of GR-binding sites located in a 200 Kb region centered on LPS-induced Dex-repressed genes in BMDM treated with Dex or LPS + Dex
Summary
Inflammation is an innate immune response to tissue injury or infection. It relies on macrophages, which recognize pathogen-associated molecular patterns and other ‘danger’ signals via their toll-like receptors (TLRs) (Glass and Saijo, 2010). This initiates a signaling cascade that leads to the activation and DNA binding of the effector transcription factors NF-kB and AP1 (O’Neill et al, 2013) which recruit coregulators, and, the basal transcription machinery that together alter the chromatin state in the vicinity of many pro-inflammatory genes and enable their transcription (Smale and Natoli, 2014; Glass and Natoli, 2015). Acute transcriptional activation of pro-inflammatory genes is, critical for overriding the homeostatic set-point and producing a robust immune response that helps to resolve infection or tissue injury (Kotas and Medzhitov, 2015)
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