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Control of transcription by core promoter elements and methyl-CpG-binding Protein 2
Abstract
Transcription is the process of copying DNA into RNA. This process is critical for transmitting the information stored in DNA to the rest of the cell. The timing and amount of transcription must be regulated in order for cells and organisms to function normally. This regulation is achieved through many levels of control. This dissertation explores regulation of transcription by core promoter elements and methyl-CpG-binding protein 2. The core promoter is a diverse and complex entity. To gain a better understanding of the core promoter, I examined the function of the motif ten element (MTE). I found that the MTE recruits TFIID to the core promoter via interactions with TAF6 and TAF9. I also performed a detailed mutational analysis of the MTE and demonstrated the importance of nucleotides in the 27-29 subregion. This analysis identified three downstream subregions (18-22, 27-29, 30- 33) that contribute to core promoter activity and led to the discovery of the novel 'Bridge' (18-22 and 30-33) core promoter motif. MeCP2 is a methyl-CpG-binding protein that is required for normal neurodevelopment. Mutations in MeCP2 cause the neurologic disorder Rett syndrome. I examined the mechanism of transcriptional repression by MeCP2 and discovered a novel, histone deacetylase- independent mechanism of repression. This mechanism involves inhibition of pre-initiation complex formation and is not dependent on a previously identified transcription repression domain. Analysis of transcription templates with specifically placed CpG dinucleotides reveals that templates with more methylation sites or with sites closer to the transcription start site are subject to stronger repression of transcription by MeCP2. These findings show that MeCP2 has a second mechanism of transcriptional repression and highlight the importance of methylation patterns in directing MeCP2 function
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