Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era.
Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era.
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DOI：
10.1016/j.jbc.2021.100687
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Sasse SK
中科院分区：
文献类型：
--
作者：
Gerber AN;Newton R;Sasse SK
糖皮质激素是一种强效抗炎药物，可用于治疗包括COVID-19在内的一系列人类疾病，这凸显了了解其分子机制的持续重要性。GR信号传导的早期研究导致糖皮质激素受体（GR）单体抑制性地拴系到炎性转录因子从而消除炎性基因表达的模型被广泛接受。然而，新的数据挑战了这一核心概念，并提供了一个令人兴奋的机会来重新构建我们对GR信号的理解。在这里，我们提出了一个替代的，两部分的糖皮质激素转录抑制模型。首先，广泛的GR介导的转录诱导导致炎症基因转录和相关增强子通过基于竞争的机制的快速、初级抑制。其次，GR诱导的基因的子集，包括与炎症转录因子如NF-κB协调调节的靶点，对炎症基因表达产生次级抑制作用。在此框架内，新出现的数据表明，通过GR和NF-κB信号传导的协同收敛调节的基因集对于糖皮质激素在终止炎症和促进组织修复方面的广泛临床有效性至关重要。
Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair.
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DOI：
10.1016/j.tem.2017.04.001
发表时间：
2017-07
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
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作者：
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DOI：
10.1007/978-1-4939-2895-8_2
发表时间：
2015-01-01
期刊：
GLUCOCORTICOID SIGNALING: FROM MOLECULES TO MICE TO MAN
影响因子：
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作者：
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影响因子：
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