Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. Academic Article uri icon

Overview

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.

publication date

  • February 9, 2018

Research

keywords

  • Gene Expression Regulation
  • Inflammation
  • Macrophages
  • Receptors, Glucocorticoid
  • Transcription, Genetic

Identity

PubMed Central ID

  • PMC5821458

Scopus Document Identifier

  • 85043534564

Digital Object Identifier (DOI)

  • 10.1186/1471-2105-11-237

PubMed ID

  • 29424686

Additional Document Info

volume

  • 7