RBFOX2失调是糖尿病心脏发病机制中的早期事件。
Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes.
作者信息
Nutter Curtis A, Jaworski Elizabeth A, Verma Sunil K, Deshmukh Vaibhav, Wang Qiongling, Botvinnik Olga B, Lozano Mario J, Abass Ismail J, Ijaz Talha, Brasier Allan R, Garg Nisha J, Wehrens Xander H T, Yeo Gene W, Kuyumcu-Martinez Muge N
机构信息
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
出版信息
Cell Rep. 2016 Jun 7;15(10):2200-2213. doi: 10.1016/j.celrep.2016.05.002. Epub 2016 May 26.
Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2-mediated AS is generated in diabetic hearts. DN RBFOX2 interacts with wild-type (WT) RBFOX2, and ectopic expression of DN RBFOX2 inhibits AS of RBFOX2 targets. Notably, DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear. Importantly, DN RBFOX2 expression impairs intracellular calcium release in cardiomyocytes. Our results demonstrate that RBFOX2 dysregulation by DN RBFOX2 is an early pathogenic event in diabetic hearts.
在糖尿病心脏中已发现对基因表达和功能产生不利影响的可变剪接（AS）缺陷；然而，其背后的机制在很大程度上尚不清楚。在此，我们表明RNA结合蛋白RBFOX2在糖尿病条件下促成了转录组变化。RBFOX2控制着在与糖尿病性心肌病相关的心脏功能中起重要作用的基因的可变剪接。尽管RBFOX2的可变剪接活性较低，但糖尿病心脏中RBFOX2蛋白水平却升高。在糖尿病心脏中产生了一种阻断RBFOX2介导的可变剪接的显性负性（DN）异构体。DN RBFOX2与野生型（WT）RBFOX2相互作用，并且DN RBFOX2的异位表达抑制了RBFOX2靶标的可变剪接。值得注意的是，DN RBFOX2的表达是糖尿病特有的，并且发生在心肌病症状出现之前的早期阶段。重要的是，DN RBFOX2的表达会损害心肌细胞内的钙释放。我们的结果表明，DN RBFOX2对RBFOX2的失调是糖尿病心脏中的一个早期致病事件。
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