小柯机器人

美国宾夕法尼亚大学Mitchell A. Lazar、Wenxiang Hu等研究人员合作揭示糖皮质激素不良代谢作用的遗传决定因素。这一研究成果于2021年7月6日在线发表在国际学术期刊《细胞—代谢》上。

通过用强效糖皮质激素（GC）地塞米松（Dex）处理多名个体脂肪干细胞衍生的脂肪细胞和诱导多能干细胞衍生的肝细胞，研究人员发现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）顺反组。个体特异性GR结合可以追溯到改变GR结合基序或其合作因子的单核苷酸多态性（SNP）。

研究人员还发现了另一组通过影响染色质可及性或染色质结构来调节Dex反应的遗传变异。几个改变Dex调节的GR结合和基因表达的SNP控制了Dex驱动的代谢扰动。

值得注意的是，这些遗传变异与接受GC治疗受试者的血清葡萄糖、脂质和体重的增加高度相关。了解使个体易产生代谢副作用的遗传变异可以采用精确的医学方法来使用临床相关的GC。

据悉，糖皮质激素（GC）被广泛用作抗炎药，但长期使用会产生严重的代谢副作用。

附：英文原文

Title: Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids

Author: Wenxiang Hu, Chunjie Jiang, Mindy Kim, Wenjian Yang, Kun Zhu, Dongyin Guan, Wenjian Lv, Yang Xiao, Jessica R. Wilson, Daniel J. Rader, Ching-Hon Pui, Mary V. Relling, Mitchell A. Lazar

Issue&Volume: 2021-07-06

Abstract: Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-termuse has severe metabolic side effects. Here, by treating multiple individual adiposestem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocyteswith the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specificGC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specificGR binding could be traced to single-nucleotide polymorphisms (SNPs) that alteredthe binding motifs of GR or its cooperating factors. We also discovered another setof genetic variants that modulated Dex response through affecting chromatin accessibilityor chromatin architecture. Several SNPs that altered Dex-regulated GR binding andgene expression controlled Dex-driven metabolic perturbations. Remarkably, these geneticvariations were highly associated with increases in serum glucose, lipids, and bodymass in subjects on GC therapy. Knowledge of the genetic variants that predisposeindividuals to metabolic side effects allows for a precision medicine approach tothe use of clinically relevant GCs.

DOI: 10.1016/j.cmet.2021.06.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00274-6

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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