title: Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner.
abstract: Ligand activation and DNA-binding dictate the outcome of glucocorticoid receptor (GR)-mediated transcriptional regulation by inducing diverse receptor conformations that interact differentially with coregulators. GR recruits many coregulators via the well-characterized AF2 interaction surface in the GR ligand-binding domain, but Lin11, Isl-1, Mec-3 (LIM) domain coregulator Hic-5 (TGFB1I1) binds to the relatively uncharacterized tau2 activation domain in the hinge region of GR. Requirement of hydrogen peroxide-inducible clone-5 (Hic-5) for glucocorticoid-regulated gene expression was defined by Hic-5 depletion and global gene-expression analysis. Hic-5 depletion selectively affected both activation and repression of GR target genes, and Hic-5 served as an on/off switch for glucocorticoid regulation of many genes. For some hormone-induced genes, Hic-5 facilitated recruitment of Mediator complex. In contrast, many genes were not regulated by glucocorticoid until Hic-5 was depleted. On these genes Hic-5 prevented GR occupancy and chromatin remodeling and thereby inhibited their hormone-dependent regulation. Transcription factor binding to genomic sites is highly variable among different cell types; Hic-5 represents an alternative mechanism for regulating transcription factor-binding site selection that could apply both within a given cell type and among different cell types. Thus, Hic-5 is a versatile coregulator that acts by multiple gene-specific mechanisms that influence genomic occupancy of GR as well transcription complex assembly.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90089.
authors.forename: Rajas
authors.initials: R
authors.lastname: Chodankar
authors.forename: Dai-Ying
authors.initials: DY
authors.lastname: Wu
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Schiller
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D060588:LIM Domain Proteins / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D008957:Models, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D011965:Receptors, Glucocorticoid; C090090:Tgfb1i1 protein, mouse
keywords: enhancer; nuclear receptor; steroid receptor