RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure.
RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure.
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DOI：
10.1016/j.tcm.2012.08.003
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发表时间：
2013-01
影响因子：
9.3
通讯作者：
Dudley, Samuel C., Jr.
中科院分区：
文献类型：
--
作者：
Gao, Ge;Dudley, Samuel C., Jr.
选择性剪接是一种转录后机制，可以显著改变基因表达模式。高达95%的人类基因具有多外显子选择性剪接形式，这表明选择性剪接是人类基因组功能复杂性的最重要组成部分之一。然而，选择性剪接调控在心脏疾病的研究中受到的关注相对较少。当研究心力衰竭中SCN 5A剪接异常时，我们发现与对照组相比，181种已知的剪接调节剂中有47种在HF中上调，这表明剪接调节可能在心力衰竭中起关键作用。我们的研究结果表明，AngII和缺氧，HF共同的信号，导致增加LUC7L3和RBM25剪接调节，增加RBM25与SCN 5A mRNA的结合，增加SCN 5A剪接变体丰度，减少全长SCN 5A mRNA和蛋白，并减少Na+电流。这些观察结果可以揭示心脏功能和糖尿病风险相关的机制，并允许精确预测哪些患者可能处于最高糖尿病风险或患有Na+通道阻断抗糖尿病药物并发症。
Alternative splicing is a post-transcriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multi-exon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure, we found 47 of 181 known splicing regulators were upregulated in HF when compared to controls, which indicate that splicing regulation may play a key role in heart failure. Our results shows that AngII and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na+ current. These observations could shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na+ channel blocking anti-arrhythmic drug complications.
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影响因子：
37.8
作者：
Inuzuka, Yasutaka;Okuda, Junji;Shioi, Tetsuo
通讯作者：
Shioi, Tetsuo
影响因子：
14.9
作者：
Modrek, B;Resch, A;Lee, C
通讯作者：
Lee, C
影响因子：
37.8
作者：
AKHTAR, M;BREITHARDT, G;ZIPES, DP
通讯作者：
ZIPES, DP
影响因子：
3.5
作者：
Nishii, Y;Morishima, M;Ueda, K
通讯作者：
Ueda, K
影响因子：
5.5
作者：
Chung, Seo-Kyung;MacCormick, Judith M.;Rees, Mark I.
通讯作者：
Rees, Mark I.