Piechota Marcin, Zieba Mateusz, Borczyk Małgorzata, Golda Slawomir, Hajto Jacek, Skupio Urszula, Slezak Michal, Parkitna Jan Rodriguez, Korostynski Michal
Laboratory of Pharmacogenomics, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, 31-343, Poland.
Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, 31-343, Poland.
BMC Genomics. 2025 May 9;26(1):462. doi: 10.1186/s12864-025-11676-w.
Glucocorticoids, acting through the glucocorticoid receptor (GR), control metabolism, maintain homeostasis, and enable adaptive responses to environmental challenges. Their function has been comprehensively studied, leading to identification of numerous tissue-specific GR-dependent mechanisms. Abundant evidence shows that GR-triggered responses differ across tissues, however, the extent of this specificity was not comprehensively explored. It is also unknown how particular GR-induced molecular patterns are translated into profile of higher-level human traits. Here, we examine cross-tissue effects of GR activation on gene expression. We assessed changes induced by stimulation with GR agonist, dexamethasone in nine tissues (adrenal cortex, perigonadal adipose tissue, hypothalamus, liver, kidney, anterior thigh muscle, pituitary gland, spleen, and lungs) in adult male C57BL/6 mice, using whole-genome microarrays. Dexamethasone induced balanced transcriptional responses across all examined tissues with 585 identified dexamethasone-regulated transcripts, including 446 with significant treatment-tissue interaction effects. Clustering analysis revealed sixteen GR-dependent patterns, including those universal across tissues and tissue-specific. We leveraged existing gene annotations and created new annotation sets based on chromatin immunoprecipitation sequencing, recent large-scale genome-wide association studies, and human transcriptome collections. As expected, GR-dependent transcripts were associated with essential metabolic processes (glycolysis/gluconeogenesis, lipid-metabolism) and inflammation-related pathways. Beyond these, we found novel links between regulated gene patterns and human phenotypic traits, like reticulocyte count or blood triglyceride levels. Overall effects of GR stimulation are well coordinated and closely linked to biological roles of tissues and organs. Our findings provide novel insights into complex systemic and tissue-specific actions of glucocorticoids and their potential impacts on human physiology and pathology.
糖皮质激素通过糖皮质激素受体（GR）发挥作用，控制新陈代谢、维持体内平衡，并使机体能够对环境挑战做出适应性反应。其功能已得到全面研究，从而确定了众多组织特异性的GR依赖机制。大量证据表明，GR引发的反应在不同组织中存在差异，然而，这种特异性的程度尚未得到全面探究。此外，目前尚不清楚特定的GR诱导分子模式是如何转化为更高级别的人类性状特征的。在此，我们研究了GR激活对基因表达的跨组织效应。我们使用全基因组微阵列评估了成年雄性C57BL/6小鼠的九个组织（肾上腺皮质、性腺周围脂肪组织、下丘脑、肝脏、肾脏、大腿前侧肌肉、垂体、脾脏和肺）中GR激动剂地塞米松刺激所诱导的变化。地塞米松在所有检测组织中诱导了平衡的转录反应，共鉴定出585个受地塞米松调控的转录本，其中包括具有显著处理-组织相互作用效应的446个转录本。聚类分析揭示了16种GR依赖模式，包括组织通用模式和组织特异性模式。我们利用现有的基因注释，并基于染色质免疫沉淀测序、近期大规模全基因组关联研究和人类转录组数据集创建了新的注释集。正如预期的那样，GR依赖的转录本与基本代谢过程（糖酵解/糖异生、脂质代谢）和炎症相关途径有关。除此之外，我们还发现了调控基因模式与人类表型特征（如网织红细胞计数或血液甘油三酯水平）之间的新联系。GR刺激的总体效应得到了很好的协调，并与组织和器官的生物学功能密切相关。我们的研究结果为糖皮质激素复杂的全身和组织特异性作用及其对人类生理和病理的潜在影响提供了新的见解。
