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首页> 外文期刊>Genome research >Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism.
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Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism.

机译：TCF7L2表达的变化定义了其作为葡萄糖代谢关键调节剂的作用。

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Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.
机译：全基因组关联研究（GWAS）一直暗示TCF7L2基因座内的非编码变异具有2型糖尿病（T2D）风险。虽然该基因座代表了人类T2D风险的最强遗传决定因素，但仍不清楚这些非编码变体如何影响疾病病因。为了测试T2D相关间隔包含控制TCF7L2表达的顺式调控元件的假设，我们进行了体内转基因报告基因检测以表征TCF7L2调控态势。我们发现与T2D相关的92-kb基因组间隔具有调节TCF7L2时空表达模式各个方面的长期增强子，包括在参与控制葡萄糖稳态的组织中的表达。通过有选择地删除此间隔，我们在健壮的TCF7L2表达中为这些增强子建立了关键的作用。为了进一步确定Tcf7l2表达的变化是否可能导致糖尿病，我们在小鼠中开发了Tcf7l2拷贝数等位基因系列。我们显示，无效的Tcf7l2等位基因以剂量依赖的方式导致降低血糖状况。 Tcf7l2无效小鼠也表现出增强的葡萄糖耐量，同时胰岛素水平明显降低，表明这些小鼠受到了T2D的保护。证实了这些观察结果，携带多个Tcf7l2拷贝并过表达该基因的转基因小鼠表现出相互的表型，包括葡萄糖耐量低下。这些结果直接表明，Tcf7l2在调节葡萄糖耐量中发挥作用，表明该基因的过表达与T2D风险增加有关。这些数据凸显了增强子元素在人类中作为T2D风险介质的作用，从而加强了证据，证明顺式调控元件的变异可能是常见疾病遗传易感性的范例。

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