Altered histone monoubiquitylation and transcriptional dysregulation
MIND researchers discover new insights into transcriptional dysregulation in HD.
Researchers at the Mass General Institute for Neurological Disease continue to find new insights into Huntington's Disease. Dr. Jang-Ho Cha and colleagues report on exciting new research which adds to our knowledge about transcriptional dysregulation in Huntington's Disease, a major pathogenic process. Their new study has shown that alteration in histone monoubiquitylation is a key mechanism. Histone monoubiquitylation is a part of the process by which specific genes are turned off and on as part of normal gene expression but not much has been known about it.
It has not been clear just exactly how the HD protein interferes with the transcription of other genes. Learning more about the steps in this process is important for finding a way to reverse it. Researchers need to identify very specific targets so that drugs can be developed in such a way that they affect only the pathogenic process and do not cause serious side effects by interacting with other molecules and cellular processes. It appears that histone monoubiquitylation has the potential to be a target for drug development.
Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation.
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.
Journal of Neuroscience 2008 Apr 9;28(15):3947-57.