Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease
- Steve Bilodeau1,
- Sophie Vallette-Kasic1,
- Yves Gauthier1,
- Dominique Figarella-Branger2,
- Thierry Brue2,
- France Berthelet3,
- André Lacroix3,
- Dalia Batista4,
- Constantine Stratakis4,
- Jeanette Hanson5,
- Björn Meij5, and
- Jacques Drouin1,6
- 1Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec H2W 1R7, Canada;
- 2Laboratoire Interactions cellulaires neuroendocriniennes (ICNE), Université de la Méditerranée, Centre national de la recherche scientifique (CNRS) UMR 6544, Institut Jean-Roche, 13385 Marseille, France;
- 3Department of Medicine, Research Center, Hotel-Dieu du Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec H2W 1T8, Canada;
- 4Section on Endocrinology and Genetics (SEGEN), Developmental Endocrinology Branch (DEB), National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland 20892, USA;
- 5Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, NL-3508-TD Utrecht, Netherlands
Abstract
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.
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Footnotes
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↵6 Corresponding author.
↵6 E-MAIL jacques.drouin{at}ircm.qc.ca; FAX (514) 987-5575.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1444606.
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- Received April 28, 2006.
- Accepted August 30, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press