Regulation of chromatin structure involves histone modifications such as acetylation. Since 1996, the identification and characterization of histone acetyltransferases have had tremendous impact on our understanding of the molecular mechanisms related to eukaryotic gene regulation and human diseases associated with abnormal chromatin functions. The MYST family of histone acetyltransferases is very interesting because of their various biological functions. In agreement with the correlation between aberrant histone acetylation and cancer, the MYST family proteins MOZ and MORF are linked to leukemogenesis. / Identification and characterization of a gene encoding a novel histone acetyltransferase were the goals of this thesis project. Human MORF gene was cloned and the encoded protein, MORF, was shown to be very similar to MOZ. Biochemical studies demonstrated that both MOZ and MORF possess intrinsic histone acetyltransferase activities. The amino- and carboxy-terminal regions of MOZ and MORF contain transcriptional repression and activation domains, respectively. / Runx2, an osteoblast-specific transcription factor, binds to the activation domains of MOZ and MORF and thus recruits them to the osteocalcin promoter for transcriptional activation. TAZ, a WW-domain transcriptional coactivator of Runx2, potentiates the transcriptional activation of the osteocalcin promoter by MOZ and Runx2. Interestingly, treatment of cells with PMA enhances the synergy between MOZ and TAZ in activating the osteocalcin promoter. Consistent with this, PMA treatment strengthens the interaction of Runx2 with MOZ and TAZ. / This study, therefore, identified the histone acetyltransferase MORF and demonstrated that MOZ and MORF are transcriptional coactivators, thus providing new insights into how histone acetyltransferases are implicated in cell differentiation and leukemogenesis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84309 |
| Date | January 2004 |
| Creators | Pelletier, Nadine |
| Contributors | Yang, Xiang-Jiao (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002141144, proquestno: AAINQ98346, Theses scanned by UMI/ProQuest. |
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