Glucocorticoid Receptor Activates Poised FKBP51 Locus through Long-Distance Interactions

Abstract

Recent studies have identified FKBP51 (FK506-binding protein 51) as a sensitive biomarker of corticosteroid responsiveness in vivo. In this work, we have elucidated the molecular mechanisms underlying the induction of FKBP51 by the glucocorticoid receptor (GR) in human A549 lung cancer cells showing robust accumulation of FKBP51 mRNA in response to dexamethasone exposure. Our quantitative chromatin immunoprecipitation scans and enhancer activity analyses indicate that activation of the FKBP51 locus by glucocorticoids in vivo is triggered by the loading of GR to enhancers at about 34 kb 5' and about 87 kb 3' of the transcription start site. Interestingly, the region encompassing these enhancers is bordered by CCCTC-binding factor- and cohesin-binding sites. Dexamethasone treatment also decreased the histone density at several regions of the gene, which was paralleled with the occupancy of SWI/SNF chromatin remodeling complexes within the locus. Moreover, silencing of BRM subunit of the SWI/SNF complex blunted the glucocorticoid induction of the locus. The proximal promoter region along with the major intronic enhancer at approximately 87 kb, at which the GR binding peaked, had elevated levels of histone 3 acetylation and H3K4 trimethylation, whereas H3K36 trimethylation more generally marked the gene body and reflected the occupancy of RNA polymerase II. The occurrence of these active chromatin marks within the FKBP51 locus before glucocorticoid exposure suggests that it is poised for transcription in A549 cells. Taken together, these results indicate that the holo-GR is capable of activating transcription and evoking changes in chromatin structure through distant-acting enhancers.