title: Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses.
abstract: Nuclear receptors (NRs) are central regulators of pathophysiological processes; however, how their responses intertwine is still not fully understood. The aim of this study was to determine whether and how steroid NRs can influence each other's activity under co-agonist treatment. We used a unique system consisting of a multicopy integration of an estrogen receptor responsive unit that allows direct visualization and quantification of estrogen receptor alpha (ERα) DNA binding, co-regulator recruitment and transcriptional readout. We find that ERα DNA loading is required for other type I nuclear receptors to be co-recruited after dual agonist treatment. We focused on ERα/glucocorticoid receptor interplay and demonstrated that it requires steroid receptor coactivators (SRC-2, SRC-3) and the mediator component MED14. We then validated this cooperative interplay on endogenous target genes in breast cancer cells. Taken together, this work highlights another layer of mechanistic complexity through which NRs cross-talk with each other on chromatin under multiple hormonal stimuli.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Michael J
authors: MJ
authors: Bolt
authors: Fabio
authors: F
authors: Stossi
authors: Justin Y
authors: JY
authors: Newberg
authors: Arturo
authors: A
authors: Orjalo
authors: Hans E
authors: HE
authors: Johansson
authors: Michael A
authors: MA
authors: Mancini
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D056892:Mediator Complex / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D011388:Prolactin / Q000235:genetics; D017433:Protein Structure, Secondary; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; C492160:MED14 protein, human; D056892:Mediator Complex; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D011965:Receptors, Glucocorticoid; D011388:Prolactin; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3