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Title: Transcriptional repression by methyl-CpG binding proteins
Author: Ng, Huck Hui
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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One approach to understand the underlying mechanisms for transcriptional repression by DNA methylation is through the study of mammalian methyl-CpG binding proteins. MeCP1 and MeCP2 are two methyl-CpG binding activities previously characterised in this laboratory. The molecular nature of MeCP1 is unknown, but the protein responsible for MeCP2 has been identified. Both in vitro and in vivo data strongly suggest that MeCP1 is a methyl-CpG dependent transcriptional repressor. MeCp2 is also a transcriptional repressor and contains a transcriptional repression domain. Recent efforts to identify other novel methyl-CpG binding proteins by searching the EST databases for proteins with methyl-CpG DNA binding domain of MeCP2 were successful. MBD1, MBD2 and MBD4 have been shown to bind specifically to methylated DNA in vitro. MBD2 is a DNA repair protein and therefore unlikely to be involved in transcriptional repression. The thesis describes collective studies of these methyl-CpG binding proteins (MeCP2, MBD1, and MBD2). MeCP2 is associated with the mSin3 corepressor complex which contains histone deacetylase subunits. Repression by the transcriptional repression domain of MeCp2 is sensitive to the histone deacetylase inhibitor, Trichostatin A (TSA), indicating that deacetylation is a critical component of the repression mechanism of MeCP2. Interestingly, MBD2 was found to be the DNA binding component of the long sought MeCP1 complex by several experimental criteria. MBD2 is also associated with histone deacetylases, and can repress transcription when tethered to the DNA. Repression of certain promoters by MBD2 can be relieved by treatment with TSA. MBD1 can also repress transcription and contains a potent repression domain. The repression by this novel domain was found to be sensitive to TSA, suggesting that deacetylation may again be involved. Altogether, these studies provide a molecular link to account for the long known relationship between DNA methylation, transcriptional repression and chromatin modification.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available