Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Neuron. 2011 Jun 23;70(6):1071-84. doi: 10.1016/j.neuron.2011.05.027.
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 coactivator 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 multifunctional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense noncoding 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 derepressed 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.
脊髓小脑共济失调 7 型（SCA7）是一种神经退行性疾病，由 ataxin-7 基因中的 CAG/多聚谷氨酰胺重复扩展引起。ataxin-7 是两个不同转录共激活复合物的组成部分，最近的工作表明，疾病蛋白在多聚谷氨酰胺神经退行性变中的正常功能发生改变。有鉴于此，我们研究了 ataxin-7 基因表达是如何调控的。ataxin-7 重复和翻译起始位点被 CTCF 的结合位点所包围，CTCF 是一种高度保守的多功能转录调节剂。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共转录的反义非编码 RNA，SCAANT1。为了了解 CTCF 如何调节 ataxin-7 基因表达，我们将 ataxin-7 迷你基因导入小鼠，并发现 CTCF 是 SCAANT1 表达所必需的。SCAANT1 的缺失以顺式依赖的方式去抑制 ataxin-7 有意义转录，并伴随着染色质重塑。这条通路的发现强调了在表现出双向转录的重复位点上，表观遗传调控改变对疾病病理学的重要性。
