Differential regulation of the SMN2 gene by individual HDAC proteins.
Differential regulation of the SMN2 gene by individual HDAC proteins.
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DOI：
10.1016/j.bbrc.2011.09.011
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发表时间：
2011-10-14
影响因子：
3.1
通讯作者：
Androphy EJ
中科院分区：
文献类型：
--
作者：
Evans MC;Cherry JJ;Androphy EJ
脊髓性肌萎缩症(SMA)是一种常染色体隐性遗传性神经退行性疾病，是婴儿死亡的主要遗传原因。SMA是由运动神经元存活基因(SMN1)纯合缺失或突变引起的。SMN2基因与SMN1基因几乎相同，但可以进行选择性剪接。与SMN1的密切关系导致SMN1成为一种非常有效的SMA疾病严重程度的遗传修饰物和治疗的靶点。我们试图确定单个HDAC蛋白用来控制SMN2基因全长蛋白表达的调控作用。我们使用定量PCR来确定单个HDAC的shRNA沉默对SMN2-荧光素酶报告转录本稳态水平的影响。我们确定，在转基因报告系统中，单个HDAC蛋白的减少足以增加SMN蛋白水平。I类HDAC蛋白的敲除通过增加启动子转录而优先激活报告。沉默第二类HDAC蛋白保持转录活性；然而，沉默HDAC 5和6似乎也增加了选择性剪接外显子的包含。这项工作突出了HDAC蛋白2和6作为优秀的研究目标。这些数据对于基本了解SMN的表达调控、改进现有的治疗化合物以及开发新的SMA治疗药物具有重要意义。
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. We sought to identify the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 genes. We used quantitative PCR to determine the effects shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
3.5
作者：
Riessland, Markus;Ackermann, Bastian;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
5.3
作者：
Riessland, Markus;Brichta, Lars;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
3.5
作者：
Lorson, CL;Androphy, EJ
通讯作者：
Androphy, EJ
影响因子：
13.3
作者：
Pandey, Udai Bhan;Batlevi, Yakup;Taylor, J. Paul
通讯作者：
Taylor, J. Paul