title: The glucocorticoid receptor and the coregulator Brm selectively modulate each other's occupancy and activity in a gene-specific manner.
abstract: The diverse transcriptional patterns that distinguish metazoan cells are specified by multifactor regulatory complexes containing distinct combinations of factors that assemble at genomic response elements. To investigate combinatorial control, we examined a set of glucocorticoid receptor (GR)-regulated genes bearing nearby regulatory complexes that include both GR and the coregulator Brm, an ATPase subunit of the Swi/Snf chromatin remodeler. We analyzed how GR and Brm affect each other's occupancy and activity by utilizing glucocorticoid treatment and Brm knockdown to modulate GR-mediated transcriptional regulation and Brm-mediated chromatin remodeling, respectively. GR occupancy and activity were altered differentially by Brm knockdown at specific activated and repressed primary GR target genes. Brm knockdown decreased GR occupancy at activated Brm-dependent genes, whereas we identified two classes of repressed genes, at which Brm knockdown either increased or decreased GR occupancy. Glucocorticoid treatment increased both Brm occupancy and chromatin accessibility at Brm-dependent and Brm-independent GR-regulated genes. However, chromatin remodeling activity decreased after Brm knockdown only at genes with Brm-dependent transcription. Our study revealed multiple distinct patterns of GR and Brm interdependence. Thus, monitoring as few as two factors within regulatory complexes is sufficient to reveal functionally distinct assemblies, providing an analytical method for gaining insights into combinatorial regulation.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Engel
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: D011965:Receptors, Glucocorticoid; C084011:SMARCA2 protein, human; D014157:Transcription Factors