Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages

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 R...

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Bibliographic Details
Published in:eLife 2018-02, Vol.7
Main Authors: Sacta, Maria A, Tharmalingam, Bowranigan, Coppo, Maddalena, Rollins, David A, Deochand, Dinesh K, Benjamin, Bradley, Yu, Li, Zhang, Bin, Hu, Xiaoyu, Li, Rong, Chinenov, Yurii, Rogatsky, Inez
Format: Article
Language:English
Subjects:
Acetylation
Analysis
Animal experimentation
Chromosomes and Gene Expression
Clonal deletion
Cytokines
Deoxyribonucleic acid
Diseases
DNA
DNA-directed RNA polymerase
Elongation
Enhancers
Enzymes
Event-related potentials
Gene deletion
Gene expression
Gene silencing
Genes
Genetic research
Genomes
Genomics
glucocorticoid receptor
Glucocorticoids
Hormones
Immunology
Immunology and Inflammation
Inflammation
Macrophages
NF-κB protein
Phosphorylation
Proteins
Recruitment
RNA
RNA polymerase
RNA Polymerase 2
Steroid hormones
Time
Transcription activation
transcription initiation and elongation
transcriptional repression
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.34864