Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes.
Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes.
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作者：
Caramori ML;Kim Y;Moore JH;Rich SS;Mychaleckyj JC;Kikyo N;Mauer M
临床研究提示代谢记忆与高血糖有关。我们测试了糖尿病是否会导致1型糖尿病（T1 D）患者与其同卵非糖尿病双胞胎相比的持续系统性体外基因表达改变。在高糖（HG）培养约6周的5对双生子皮肤成纤维细胞（SFs）中测定微阵列基因表达。探索性视觉分析系统测试了KEGG（京都基因和基因组百科全书）途径内基因表达水平的组差异。在八个途径中发现了过多的差异表达基因：花生四烯酸代谢（P = 0.003849），转化生长因子-β信号（P = 0.009167），谷胱甘肽代谢（P = 0.01281），糖基磷脂酰肌醇锚（P = 0.01949）、粘附连接（P = 0.03134）、背腹轴形成（P = 0.03695）、蛋白酶体（P = 0.04327）以及补体和凝血级联（P = 0.04666）。参与表观遗传机制的几个基因也有差异表达。所有差异表达的途径和所有表观遗传学相关的差异表达基因先前都与体外HG或动物和人类研究中的糖尿病及其并发症相关。然而，这是第一个体外研究证明T1 D不一致同卵双胞胎之间的糖尿病相关基因表达差异。这些SF基因表达差异，尽管HG在体外条件下持续存在，可能反映了“代谢记忆”，因此不一致的同卵双胞胎代表了研究人类糖尿病表观遗传过程的极好模型。
Clinical studies suggest metabolic memory to hyperglycemia. We tested whether diabetes leads to persistent systematic in vitro gene expression alterations in patients with type 1 diabetes (T1D) compared with their monozygotic, nondiabetic twins. Microarray gene expression was determined in skin fibroblasts (SFs) of five twin pairs cultured in high glucose (HG) for ∼6 weeks. The Exploratory Visual Analysis System tested group differences in gene expression levels within KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. An overabundance of differentially expressed genes was found in eight pathways: arachidonic acid metabolism (P = 0.003849), transforming growth factor-β signaling (P = 0.009167), glutathione metabolism (P = 0.01281), glycosylphosphatidylinositol anchor (P = 0.01949), adherens junction (P = 0.03134), dorsal-ventral axis formation (P = 0.03695), proteasome (P = 0.04327), and complement and coagulation cascade (P = 0.04666). Several genes involved in epigenetic mechanisms were also differentially expressed. All differentially expressed pathways and all the epigenetically relevant differentially expressed genes have previously been related to HG in vitro or to diabetes and its complications in animal and human studies. However, this is the first in vitro study demonstrating diabetes-relevant gene expression differences between T1D-discordant identical twins. These SF gene expression differences, persistent despite the HG in vitro conditions, likely reflect “metabolic memory”, and discordant identical twins thus represent an excellent model for studying diabetic epigenetic processes in humans.
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