Title | Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Sacta MA, Tharmalingam B, Coppo M, Rollins DA, Deochand DK, Benjamin B, Yu L, Zhang B, Hu X, Li R, Chinenov Y, Rogatsky I |
Journal | Elife |
Volume | 7 |
Date Published | 2018 Feb 09 |
ISSN | 2050-084X |
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. |
DOI | 10.7554/eLife.34864 |
Alternate Journal | Elife |
PubMed ID | 29424686 |
PubMed Central ID | PMC5821458 |
Grant List | PR130049 / / U.S. Department of Defense / R01 DK099087 / DK / NIDDK NIH HHS / United States T32GM007739 / / National Institutes of Health / 81571580 / / National Natural Science Foundation of China / 8151101184 / / National Natural Science Foundation of China / R01DK099087 / / National Institutes of Health / 81422019 / / National Natural Science Foundation of China / R01 CA220578 / / National Institutes of Health / R01 CA220578 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States 91642115 / / National Natural Science Foundation of China / |
Submitted by kej2006 on June 6, 2018 - 4:10pm