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1 Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec H2W 1R7, Canada; 2 Laboratoire Interactions cellulaires neuroendocriniennes (ICNE), Université de la Méditerranée, Centre national de la recherche scientifique (CNRS) UMR 6544, Institut Jean-Roche, 13385 Marseille, France; 3 Department of Medicine, Research Center, Hotel-Dieu du Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec H2W 1T8, Canada; 4 Section on Endocrinology and Genetics (SEGEN), Developmental Endocrinology Branch (DEB), National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland 20892, USA; 5 Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, NL-3508-TD Utrecht, Netherlands
Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo–pituitary–adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that 
50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process.
[Keywords: Repression; nuclear receptor; Swi/Snf; pituitary tumors; POMC; Cushing]
Received April 28, 2006; revised version accepted August 30, 2006.
E-MAIL jacques.drouin{at}ircm.qc.ca; FAX (514) 987-5575.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1444606.
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