title: Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor.
abstract: The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex "negative" GREs (nGREs) has been reported. However, GR-mediated transrepression was generally ascribed to indirect "tethered" interaction with other DNA-bound factors. We report that GC-induces direct transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Université de Strasbourg, Collège de France, Illkirch, 67404, France.
authors.forename: Milan
authors.initials: M
authors.lastname: Surjit
authors.forename: Krishna Priya
authors.initials: KP
authors.lastname: Ganti
authors.forename: Atish
authors.initials: A
authors.lastname: Mukherji
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
mesh_terms: D000818:Animals; D016207:Cytokines; D003876:Dermatitis, Atopic / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D000094632:Thymic Stromal Lymphopoietin