Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease.
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 approximately 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.
Bilodeau
Steve
S
Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec H2W 1R7, Canada.
Vallette-Kasic
Sophie
S
Gauthier
Yves
Y
Figarella-Branger
Dominique
D
Brue
Thierry
T
Berthelet
France
F
Lacroix
André
A
Batista
Dalia
D
Stratakis
Constantine
C
Hanson
Jeanette
J
Meij
Björn
B
Drouin
Jacques
J
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism / Q000502:physiology*; D004285:Dogs; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics* / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D006657:Histones; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; C084108:SMARCA4 protein, human; D004265:DNA Helicases