Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle.
Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-κB and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR:GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle.
Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Rebecca
R
Gupte
Ginger W
GW
Muse
Yurii
Y
Chinenov
Karen
K
Adelman
Inez
I
Rogatsky
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C491309:Grip1 protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C118437:negative elongation factor; D003907:Dexamethasone; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II
NELF and P-TEFb complex; inflammation; initiation and elongation; transcriptional repression