Altered histone monoubiquitylation mediated by mutant Huntingtin induces transcriptional dysregulation
Altered histone monoubiquitylation mediated by mutant Huntingtin induces transcriptional dysregulation
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DOI：
10.1523/jneurosci.5667-07.2008
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发表时间：
2008-04-09
影响因子：
5.3
通讯作者：
Cha, Jang-Ho J.
中科院分区：
文献类型：
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作者：
Kim, Mee-Ohk;Chawla, Prianka;Cha, Jang-Ho J.
虽然转录调控异常是亨廷顿病（HD）的一个重要致病机制，但突变的亨廷顿蛋白是如何引起HD的还不清楚。亨廷顿蛋白与Bmi-1（hPRC 1 L E3遍在蛋白连接酶复合物的一种组分）的相互作用被破坏，会增加HD细胞培养模型中单脲基组蛋白H2 A（uH 2 A）的水平。在转基因R6/2小鼠脑中表达被抑制的基因在其启动子处具有增加的uH 2A和减少的uH 2B，而活跃转录的基因显示相反的模式。uH 2A的减少逆转转录抑制并抑制细胞培养物中组蛋白H3在赖氨酸9处的甲基化。相反，uH 2B的减少诱导转录抑制并抑制组蛋白H3在赖氨酸4处的甲基化。这是第一个报告，证明hPRC 1 L作为一个亨廷顿相互作用的组蛋白修饰复合物和组蛋白monoubiquitylation在哺乳动物脑基因表达的关键作用，这拓宽了我们的理解组蛋白密码。这些发现也为靶向组蛋白单泛素化治疗HD提供了理论基础。
Although transcriptional dysregulation is a critical pathogenic mechanism in Huntington's disease (HD), it is still not known how mutant huntingtin causes it. Here we show that alteration of histone monoubiquitylation is a key mechanism. Disrupted interaction of huntingtin with Bmi-1, a component of the hPRC1L E3 ubiquitin ligase complex, increases monoubiquityl histone H2A (uH2A) levels in a cell culture model of HD. Genes with expression that is repressed in transgenic R6/2 mouse brain have increased uH2A and decreased uH2B at their promoters, whereas actively transcribed genes show the opposite pattern. Reduction in uH2A reverses transcriptional repression and inhibits methylation of histone H3 at lysine 9 in cell culture. In contrast, reduction in uH2B induces transcriptional repression and inhibits methylation of histone H3 at lysine 4. This is the first report to demonstrate hPRC1L as a huntingtin-interacting histone modifying complex and a crucial role for histone monoubiquitylation in mammalian brain gene expression, which broadens our understanding of histone code. These findings also provide a rationale for targeting histone monoubiquitylation for therapy in HD.