Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease
Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease
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DOI：
10.1101/gad.1444606
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发表时间：
2006-10-15
影响因子：
10.5
通讯作者：
Drouin, Jacques
中科院分区：
文献类型：
--
作者：
Bilodeau, Steve;Vallette-Kasic, Sophie;Drouin, Jacques
阿黑皮素原（proopiomelanocortin，POMC）基因受糖皮质激素受体（glucocorticoid receptor，GR）负反馈调节是下丘脑-垂体-肾上腺轴的重要特征，部分是由GR与NGFI-B相关的孤儿核受体之间的反式阻遏作用实现的。我们现在表明，Brg 1，ATP酶亚基的Swi/Snf复合物，是必不可少的这种反式阻遏，Brg 1是需要在体内稳定GR和NGFI-B之间的相互作用，以及GR和HDAC 2之间。而Brg 1是组成性存在于POMC启动子，GR和HDAC 2的招聘是配体依赖性的，并导致组蛋白H4的POMC基因座的脱乙酰化。此外，GR依赖性抑制抑制启动子清除RNA聚合酶II。因此，在启动子和染色质修饰的阻遏物和激活剂的共募集共同有助于GR和NGFI-B之间的直接相互作用启动的反式阻遏。因此，Brg 1或HDAC 2的缺失应产生GC抗性，我们发现类似于50%的GC抗性的人类和狗促肾上腺皮质激素细胞腺瘤，这是库欣病的标志，缺乏核表达的蛋白质。除了为GC抗性提供分子基础之外，这些缺陷也可能有助于肿瘤发生过程。
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 similar to 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.