Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 09, 2018
- Source ID
- 10.7554/elife.34864
Entities
People
- Bin Zhang
- Bowranigan Tharmalingam
- Bradley Benjamin
- David A. Rollins
- Dinesh K Deochand
- Inez Rogatsky
- Li Yu
- Maddalena Coppo
- Maria A Sacta
- Rong Li
- Xiaoyu Hu
- Yurii Chinenov
Organizations
- American College of Rheumatology Research and Education Foundation
- Hospital for Special Surgery
- Ministry of Science and Technology of the People's Republic of China
- National Institutes of Health
- National Natural Science Foundation of China
- Tsinghua University
- United States Department of Defense
- University of Texas Health Science Center at San Antonio
- Weill Cornell Medicine