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- Title
Altered Histone Monoubiquitylation Mediated by Mutant Huntingtin Induces Transcriptional Dysregulation.
- Authors
Mee-Ohk Kim; Chawla, Prianka; Overland, Ryan P.; Xia, Eva; Sadri-Vakili, Ghazaleh; Jang-Ho J. Cha
- Abstract
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 histoneH2A(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.
- Subjects
HISTONES; GENETIC transcription; HUNTINGTON disease; CELL culture; METHYLATION; GENE expression
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 15, p3947
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5667-07.2008