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The Journal of Neuroscience, April 9, 2008, 28(15):3947-3957; doi:10.1523/JNEUROSCI.5667-07.2008

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Neurobiology of Disease
Altered Histone Monoubiquitylation Mediated by Mutant Huntingtin Induces Transcriptional Dysregulation

Mee-Ohk Kim, Prianka Chawla, Ryan P. Overland, Eva Xia, Ghazaleh Sadri-Vakili, and Jang-Ho J. Cha

MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Jang-Ho J. Cha, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129. Email: cha{at}helix.mgh.harvard.edu

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.

Key words: histone monoubiquitylation; huntingtin; Bmi-1; histone methylation; transcription; histone code

Received Sept. 19, 2007; revised Feb. 4, 2008; accepted Feb. 11, 2008.

Correspondence should be addressed to Dr. Jang-Ho J. Cha, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129. Email: cha{at}helix.mgh.harvard.edu






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