TY - JOUR TI - Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages AU - Sacta, Maria A AU - Tharmalingam, Bowranigan AU - Coppo, Maddalena AU - Rollins, David A AU - Deochand, Dinesh K AU - Benjamin, Bradley AU - Yu, Li AU - Zhang, Bin AU - Hu, Xiaoyu AU - Li, Rong AU - Chinenov, Yurii AU - Rogatsky, Inez A2 - Tontonoz, Peter VL - 7 PY - 2018 DA - 2018/02/09 SP - e34864 C1 - eLife 2018;7:e34864 DO - 10.7554/eLife.34864 UR - https://doi.org/10.7554/eLife.34864 AB - 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. KW - inflammation KW - macrophages KW - glucocorticoid receptor KW - transcriptional repression KW - transcription initiation and elongation KW - RNA Polymerase 2 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -