Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction.
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DOI：
10.1371/journal.pbio.0040067
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发表时间：
2006-03
期刊：
影响因子：
9.8
通讯作者：
Devys D
中科院分区：
文献类型：
--
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
脊髓小脑性共济失调 7 型 (SCA7) 是由聚谷氨酰胺 (polyQ) 扩张引起的几种遗传性神经退行性疾病之一，但它是唯一一种视网膜受到影响的疾病。越来越多的证据表明转录改变有助于 polyQ 发病机制，尽管其机制尚不清楚。我们之前证明，SCA7 基因产物 ataxin-7 (ATXN7) 是含有 GCN5 组蛋白乙酰转移酶的共激活复合物 TTC/STAGA 的一个亚基。我们在此表明，从 SCA7 小鼠中纯化的 TTC/STAGA 复合物具有正常的 TRRAP、GCN5、TAF12 和 SPT3 水平，并且它们的组蛋白或核小体乙酰化活性不受影响。然而，SCA7 小鼠模型的视杆光感受器显示出严重的染色质去浓缩。一致地，polyQ 扩增的 ataxin-7 诱导组蛋白 H3 过度乙酰化，这是由于 TTC/STAGA 向特定启动子的募集增加所致。令人惊讶的是，超乙酰化基因转录下调，表达分析显示几乎所有视杆细胞特异性基因都受到影响，导致 SCA7 小鼠出现视力障碍。总之，我们在这里描述了一组解释视网膜中SCA7发病机制的事件，其中polyQ扩展的ATXN7解除了TFTC/STAGA募集到杆状光感受器中特异性表达的基因子集的调节，导致染色质改变并随后逐渐丧失杆状光感受器功能。脊髓小脑共济失调 7 型 (SCA7) 小鼠模型为了解导致这种神经退行性疾病的转录改变提供了新的见解。
Spinocerebellar ataxia type 7 (SCA7) is one of several inherited neurodegenerative disorders caused by a polyglutamine (polyQ) expansion, but it is the only one in which the retina is affected. Increasing evidence suggests that transcriptional alterations contribute to polyQ pathogenesis, although the mechanism is unclear. We previously demonstrated that theSCA7 gene product, ataxin-7 (ATXN7), is a subunit of the GCN5 histone acetyltransferase–containing coactivator complexes TFTC/STAGA. We show here that TFTC/STAGA complexes purified from SCA7 mice have normal TRRAP, GCN5, TAF12, and SPT3 levels and that their histone or nucleosomal acetylation activities are unaffected. However, rod photoreceptors from SCA7 mouse models showed severe chromatin decondensation. In agreement, polyQ-expanded ataxin-7 induced histone H3 hyperacetylation, resulting from an increased recruitment of TFTC/STAGA to specific promoters. Surprisingly, hyperacetylated genes were transcriptionally down-regulated, and expression analysis revealed that nearly all rod-specific genes were affected, leading to visual impairment in SCA7 mice. In conclusion, we describe here a set of events accounting for SCA7 pathogenesis in the retina, in which polyQ-expanded ATXN7 deregulated TFTC/STAGA recruitment to a subset of genes specifically expressed in rod photoreceptors, leading to chromatin alterations and consequent progressive loss of rod photoreceptor function. A mouse model of Spinocerebellar ataxia type 7 (SCA7) offers new insight into transcriptional alterations that contribute to this neurodegenerative disorder.
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