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

Maria A. Sacta, Bowranigan Tharmalingam, Maddalena Coppo, David A. Rollins, Dinesh K. Deochand, Bradley Benjamin, Li Yu, Bin Zhang, Xiaoyu Hu, Rong Li, Yurii Chinenov, Inez Rogatsky

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere34864
JournaleLife
Volume7
DOIs
StatePublished - Feb 9 2018

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Macrophages
Glucocorticoid Receptors
Genes
Glucocorticoids
NF-kappa B
Acetylation
Myeloid Cells
DNA-Directed RNA Polymerases
Histones
Machinery
Binding Sites
Elongation
Genome
Inflammation
Chemical activation
negative elongation factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Sacta, M. A., Tharmalingam, B., Coppo, M., Rollins, D. A., Deochand, D. K., Benjamin, B., ... Rogatsky, I. (2018). Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. eLife, 7, [e34864]. https://doi.org/10.7554/eLife.34864

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

In: eLife, Vol. 7, e34864, 09.02.2018.

Research output: Contribution to journalArticle

Sacta, MA, Tharmalingam, B, Coppo, M, Rollins, DA, Deochand, DK, Benjamin, B, Yu, L, Zhang, B, Hu, X, Li, R, Chinenov, Y & Rogatsky, I 2018, 'Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages', eLife, vol. 7, e34864. https://doi.org/10.7554/eLife.34864
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. / Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. In: eLife. 2018 ; Vol. 7.
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