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• W2078111498 startingPage "2871" @default.
• W2078111498 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." @default.
• W2078111498 created "2016-06-24" @default.
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• W2078111498 date "2006-10-15" @default.
• W2078111498 modified "2023-10-14" @default.
• W2078111498 title "Role of Brg1 and HDAC2 in GR <i>trans</i>-repression of the pituitary <i>POMC</i> gene and misexpression in Cushing disease" @default.
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• W2078111498 doi "https://doi.org/10.1101/gad.1444606" @default.
• W2078111498 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1619949" @default.
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