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首页> 外文期刊>Genes and Development: a Journal Devoted to the Molecular Analysis of Gene Expression in Eukaryotes, Prokaryotes, and Viruses >DOT1L regulates dystrophin expression and is critical for cardiac function.
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DOT1L regulates dystrophin expression and is critical for cardiac function.

机译：DOT1L调节肌营养不良蛋白的表达，对心脏功能至关重要。

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摘要

Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin-glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease.
机译：组蛋白甲基化在调节基因表达中起重要作用。一种这样的甲基化发生在组蛋白H3（H3K79）的Lys 79处，并由酵母DOT1（端粒沉默的破坏者）及其哺乳动物同源物DOT1L催化。先前的研究表明，小鼠Dot1L的种系破坏会导致胚胎致死率。在这里我们报告说，Dot1L的心脏特异性敲除导致室扩张的死亡率增加，心肌细胞死亡增加，收缩功能障碍和传导异常。这些表型模仿了扩张型心肌病（DCM）患者所表现的表型。机理研究表明，DOT1L通过调节肌营养不良蛋白（Dmd）的转录，从而在心肌细胞中发挥其功能，因此，对于心肌细胞活力至关重要的肌营养不良蛋白-糖蛋白复合物的稳定性也得到改善。重要的是，miniDmd的表达可以在很大程度上挽救DCM表型，表明Dmd是介导心肌细胞DOT1L功能的主要靶标。有趣的是，对可用基因表达数据集的分析表明，与正常对照相比，特发性DCM患者样品中DOT1L的表达下调。因此，我们的研究不仅确定了DOT1L介导的H3K79甲基化在心肌细胞功能中的关键作用，而且揭示了DOT1L在DCM中的作用机理。此外，我们的研究可能会为诊断和治疗人类心脏病开辟新的途径。

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