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首页> 外文期刊>Molecular and Cellular Biology >Ligand-Induced Repression of the Glucocorticoid Receptor Gene Is Mediated by an NCoR1 Repression Complex Formed by Long-Range Chromatin Interactions with Intragenic Glucocorticoid Response Elements
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Ligand-Induced Repression of the Glucocorticoid Receptor Gene Is Mediated by an NCoR1 Repression Complex Formed by Long-Range Chromatin Interactions with Intragenic Glucocorticoid Response Elements

机译：糖皮质激素受体基因的配体诱导的阻遏是由NCoR1阻遏复合物介导的，该复合物由长效染色质与基因内糖皮质激素响应元素相互作用而形成。

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Glucocorticoids are among the most potent and effective agents for treating inflammatory diseases and hematological cancers. However, subpopulations of patients are often resistant to steroid therapy, and determining the molecular mechanisms that contribute to glucocorticoid resistance is thus critical to addressing this clinical problem affecting patients with chronic inflammatory disorders. Since the cellular level of the glucocorticoid receptor (GR) is a critical determinant of glucocorticoid sensitivity and resistance, we investigated the molecular mechanisms mediating repression of glucocorticoid receptor gene expression. We show here that glucocorticoid-induced repression of GR gene expression is mediated by inhibition of transcription initiation. This process is orchestrated by the recruitment of agonist-bound GR to exon 6, followed by the assembly of a GR-NCoR1-histone deacetylase 3-containing repression complex at the transcriptional start site of the GR gene. A functional negative glucocorticoid response element (nGRE) in exon 6 of the GR gene and a long-range interaction occurring between this intragenic response element and the transcription start site appear to be instrumental in this repression. This autoregulatory mechanism of repression implies that the GR concentration can coordinate repression with excess ligand, regardless of the combinatorial associations of tissue-specific transcription factors. Consequently, the chronic nature of inflammatory conditions involving long-term glucocorticoid administration may lead to constitutive repression of GR gene transcription and thus to glucocorticoid resistance.
机译：糖皮质激素是治疗炎性疾病和血液学癌症的最有效和有效的药物之一。然而，患者亚群通常对类固醇疗法有抗性，因此确定促成糖皮质激素抗性的分子机制因此对于解决影响患有慢性炎性疾病的患者的这一临床问题至关重要。由于糖皮质激素受体（GR）的细胞水平是糖皮质激素敏感性和耐药性的关键决定因素，因此我们研究了介导糖皮质激素受体基因表达抑制的分子机制。我们在这里显示，糖皮质激素诱导的GR基因表达的抑制是通过抑制转录起始介导的。通过将激动剂结合的GR募集到第6外显子，然后在GR基因的转录起始位点组装包含GR-NCoR1-组蛋白脱乙酰基酶3的阻遏复合物，来协调此过程。 GR基因外显子6中的功能性糖皮质激素阴性反应元件（nGRE）以及该基因内反应元件与转录起始位点之间发生的远程相互作用似乎在这种抑制中起着重要作用。这种抑制的自动调节机制意味着GR浓度可以与过量配体协调抑制，而与组织特异性转录因子的组合关联无关。因此，涉及长期给予糖皮质激素的炎症性疾病的慢性性质可能导致GR基因转录的组成型抑制，从而导致糖皮质激素抵抗。

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