CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.
CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.
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DOI：
10.1016/j.neuron.2011.05.027
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发表时间：
2011-06-23
期刊：
影响因子：
16.2
通讯作者：
La Spada AR
中科院分区：
文献类型：
--
作者：
Sopher BL;Ladd PD;Pineda VV;Libby RT;Sunkin SM;Hurley JB;Thienes CP;Gaasterland T;Filippova GN;La Spada AR
脊髓小脑性共济失调7型（SCA 7）是一种神经退行性疾病引起的CAG /聚谷氨酰胺重复扩增在共济失调蛋白-7基因。共济失调蛋白-7是两种不同的转录共激活因子复合物的组成部分，最近的研究表明，疾病蛋白的正常功能在多聚谷氨酰胺神经变性中发生了改变。鉴于此，我们研究了ataxin-7基因的表达是如何调节的。共济失调蛋白-7重复序列和翻译起始位点两侧是CTCF的结合位点，CTCF是一种高度保守的多功能转录调节因子。当我们分析这个区域时，我们发现了一个相邻的替代启动子和一个收敛转录的反义非编码RNA SCAANT 1。为了了解CTCF如何调节ataxin-7基因表达，我们将ataxin-7微基因导入小鼠，发现CTCF是SCAANT 1表达所必需的。SCAANT 1的丢失以顺式依赖的方式去抑制共济失调蛋白-7的正义转录，并伴随着染色质重塑。这一途径的发现强调了在呈现双向转录的重复位点改变的表观遗传调节对疾病病理的重要性。
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG / polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription co-activator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multi-functional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense non-coding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 de-repressed ataxin-7 sense transcription in a cis-dependent fashion, and was accompanied by chromatin remodeling. Discovery of this pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription.
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影响因子：
9.8
作者：
Helmlinger D;Hardy S;Abou-Sleymane G;Eberlin A;Bowman AB;Gansmüller A;Picaud S;Zoghbi HY;Trottier Y;Tora L;Devys D
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Devys D
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