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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function
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Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

机译：转录因子KLF11及其糖尿病相关基因变异在胰腺β细胞功能中的作用

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摘要

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.
机译：KLF11（TIEG2）是一种富含胰腺的转录因子，由于其在体外和体内作为外分泌细胞生长的负调节剂而引起广泛关注。然而，其在内分泌胰腺中的功能作用尚待确定。在这里，我们首次向我们报告了KLF11作为胰岛素基因的葡萄糖诱导型调节剂的特征。随机寡核苷酸结合，EMSA，萤光素酶报道基因和染色质免疫沉淀试验的组合显示，KLF11与胰岛素启动子结合并调节其在β细胞中的活性。对KLF11基因的遗传分析显示，有两种罕见的变体（Ala347Ser和Thr220Met）与早发2型糖尿病的家庭与糖尿病隔离，并显着削弱其转录活性。此外，对1,696位2型糖尿病和1,776名正常血糖受试者的分析显示，常见的多态性Gln62Arg变异与北欧人群中的2型糖尿病显着相关（OR = 1.29，P = 0.00033）。此外，该变体改变了KLF11的核心抑制剂mSin3A结合活性，损害了胰岛素启动子的激活，并在胰腺β细胞中显示出较低水平的胰岛素表达。另外，携带Gln62Arg等位基因的受试者在口服葡萄糖激发后显示血浆胰岛素降低。有趣的是，所有三个非同义的KLF11变体均表现出对过氧化氢酶1启动子的抑制作用的增强，表明在自由基清除中的作用可能使β细胞对氧化应激更加敏感。因此，功能和遗传分析均显示KLF11在胰腺β细胞生理调节中发挥作用，其变体可能有助于糖尿病的发展。

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