Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Max-Planck Center for Tissue Stem Cell Research and Regenerative Medicine, Bioland Laboratory, Guangzhou, China.
Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Metab. 2021 Aug 3;33(8):1592-1609.e7. doi: 10.1016/j.cmet.2021.06.004. Epub 2021 Jul 6.
Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.
糖皮质激素（GCs）被广泛用作抗炎药物，但长期使用会产生严重的代谢副作用。在这里，我们通过用强效 GC 地塞米松（Dex）处理多个个体脂肪干细胞来源的脂肪细胞和诱导多能干细胞来源的肝细胞，揭示了细胞类型特异性和个体特异性 GC 依赖性转录组和糖皮质激素受体（GR）顺式作用元件组。个体特异性 GR 结合可以追溯到单核苷酸多态性（SNP），这些 SNP 改变了 GR 或其协同因子的结合基序。我们还发现了另一组遗传变异，通过影响染色质可及性或染色质结构来调节 Dex 反应。一些 SNP 改变了 Dex 调节的 GR 结合和基因表达，控制了 Dex 驱动的代谢紊乱。值得注意的是，这些遗传变异与接受 GC 治疗的患者血清葡萄糖、脂质和体重增加高度相关。了解使个体易发生代谢副作用的遗传变异，可以为使用临床相关 GCs 的精准医疗方法提供依据。
