Graduate Thesis Or Dissertation
 

Transcriptional repression by CTIP2, a C2H2 zinc finger protein

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  • CTIP2, a novel C2H2 zinc finger protein, is a transcriptional repressor that functions by at least two mechanisms. CTIP2 interacts with and stimulates transcriptional repression mediated by COUP-TF family members. CTIP2 also represses transcription independently of COUP-TF proteins by direct, sequence-specific DNA binding activity. CTIP2 has been implicated in lymphoid malignancies and development of T lymphocytes and the central nervous system (CNS). However, very little is known concerning the molecular mechanism(s) by which CTIP2 functions in these processes. The goal of the studies described herein was to contribute towards a greater understanding of cellular functions of CTIP2 through the characterization of domains of CTIP2 required for transcriptional regulatory activity, identification of CTIP2 target genes, and elucidation of molecular mechanisms underlying the transcriptional repression mediated by CTIP2. CTIP2 was found to repress transcription by recruiting at least three different histone deacetylases (HDAC) to the promoter template of target genes. The three HDACs that were identified as being involved in CTIP2-mediated transcriptional repression were SIRT1, HDAC1, and HDAC2. The latter two were found in the same complex, which we identified as the Nucleosome Remodeling and Deacetylation (NuRD) complex. The SIRT1 and NuRD complexes appeared to be differentially recruited to CTIP2 target genes as a function of promoter, and possibly cellular, context. CTIP2 was found to recruit the NuRD complex, but not the SIRT1 complex, to the promoter of the cyclin-dependent kinase inhibitor p57KIP2 gene, a new transcriptional target of CTIP2 in neuroblastoma cells. By analyses of regions of CTIP2 required for functionality, we found that the C-terminal zinc finger (ZnF) 5-7 module conferred self-associative activity, which appeared to be obligatory for high-affinity DNA binding and transcriptional repression of the protein. In contrast, the centrally located ZnF3-4 module of CTIP2 may confer sequence-specific DNA binding activity. The results described herein provide a framework for understanding the mechanisms underlying the transcriptional regulatory activity of CTIP2, which may contribute to a better understanding of molecular and cellular basis for the activity of CTIP2 in vivo.
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