Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver.
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver.
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DOI：
10.1371/journal.pgen.1009737
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发表时间：
2021-08
期刊：
影响因子：
4.5
通讯作者：
Conway-Campbell BL
中科院分区：
文献类型：
--
作者：
Flynn BP;Birnie MT;Kershaw YM;Pauza AG;Kim S;Baek S;Rogers MF;Paterson AR;Stavreva DA;Murphy D;Hager GL;Lightman SL;Conway-Campbell BL
超糖皮质激素节律在哺乳动物物种中是高度保守的，然而，其功能意义尚未完全了解。在这里，我们证明了肾上腺切除大鼠的脉动性皮质酮替代在脉冲峰值时诱导肝脏中约3000个基因组位点的糖皮质激素受体（GR）结合的动态模式，随后在脉冲最低点时没有发现。相反，经常更换皮质酮会导致大多数这些位点的结合时间延长。此外，每种模式进一步诱导显著不同的转录反应。在脉冲处理期间，活性RNA聚合酶II的基因内占用表现出脉冲动力学，随着基因的短暂变化，富集或减少或增加，在脉冲间隔期间大部分恢复到基线水平。相反，持续的皮质酮暴露会对大多数基因靶点的RNA聚合酶II占用产生长期影响，从而作为糖皮质激素靶基因的反式激活和抑制的持续调节信号。因此，这些差异的净效应在肝脏转录组中被观察到，RNA-seq分析表明，尽管输注皮质酮的总量相同，但与脉动相比，持续输注皮质酮可调节转录本数量的两倍。被发现以模式依赖的方式差异调节的靶基因在包括碳水化合物、胆固醇、葡萄糖和脂肪代谢以及炎症在内的功能途径中富集，这表明糖皮质激素节律失调在代谢功能障碍的发展中具有功能作用。肾上腺糖皮质激素以一种特征性的超昼夜节律释放，在慢性应激、疾病或合成皮质类固醇治疗期间变得失调。代谢功能障碍是与所有这些疾病相关的合并症，但糖皮质激素动力学改变的作用尚不清楚。由于肝脏是糖皮质激素作用于由糖皮质激素受体调节的代谢稳态的主要部位，我们已经评估了肾上腺切除大鼠的不同激素替代模式如何通过改变糖皮质激素受体与调节位点结合的模式来不同地调节涉及II型糖尿病、肝硬化和脂肪肝发展的基因通路。我们相信我们的研究结果对治疗具有重要意义，可以再现内源性糖皮质激素节律，从而最大限度地减少患者的不良代谢副作用。
Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction. Adrenal glucocorticoid hormones are released in a characteristic ultradian rhythm that becomes dysregulated during chronic stress, disease, or synthetic corticosteroid treatment. Metabolic dysfunction is a comorbidity associated with all these conditions, but the role that altered glucocorticoid dynamics play is unknown. As the liver is a major site of glucocorticoid action on metabolic homeostasis regulated by the glucocorticoid receptor, we have assessed how different patterns of hormone replacement in adrenalectomised rats differentially regulate gene pathways involved in type II diabetes, cirrhosis, and fatty liver development, via altering the pattern of glucocorticoid receptor binding to regulatory sites. We believe our findings have important implications for therapies that can reproduce the endogenous glucocorticoid rhythm and thus minimize adverse metabolic side-effects in patients.
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影响因子：
16
作者：
Ahn, SH;Kim, M;Buratowski, S
通讯作者：
Buratowski, S
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1515/hmbci-2014-0021
发表时间：
2014-08-01
影响因子：
1
作者：
de Guia, Roldan M.;Rose, Adam J.;Herzig, Stephan
通讯作者：
Herzig, Stephan
影响因子：
4.1
作者：
George, Charlotte L.;Birnie, Matthew T.;Flynn, Benjamin P.;Kershaw, Yvonne M.;Lightman, Stafford L.;Conway-Campbell, Becky L.
通讯作者：
Conway-Campbell, Becky L.
影响因子：
3.2
作者：
Conway-Campbell BL;Sarabdjitsingh RA;McKenna MA;Pooley JR;Kershaw YM;Meijer OC;de Kloet ER;Lightman SL
通讯作者：
Lightman SL