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Dissertation
Tip60 and APP genetically interact to promote apoptosis-driven neurodegeneration
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2010
DOI:
https://doi.org/10.17918/etd-3418
Abstract
Chromatin packaging in the nucleus of eukaryotic cells is a dynamic process controlled by specific post-translational modifications of histone proteins. One such modification, acetylation, is catalyzed by histone acetyltransferase (HAT) enzymes, and serves to regulate chromatin condensation that promotes gene control. The HAT Tip60 plays a central role in developmental gene control, yet the specific cellular pathways that are regulated exclusively by the epigenetic based HAT activity of Tip60 remain to be identified. We have developed a system in transgenic Drosophila that allows for targeted and inducible production of dominant negative HAT defective Dmel\TIP60 in specific tissues and developmental stages. Such flies are a powerful experimental tool to exclusively explore the epigenetic dependency of cellular processes involving Tip60. Ubiquitous expression of dominant negative Tip60 results in lethality that is rescued by additional wild-type Dmel\TIP60, indicating that Tip60 HAT activity is essential for multicellular development, and specifically for nervous system function. We have exploited this system to identify novel gene targets that are controlled by Tip60 HAT activity using microarray analysis. Our results show that Tip60 HAT activity regulates genes involved in many cellular pathways previously unlinked to Tip60, and highlight a tissue-specific enrichment of genes involved in neuronal development. To further assess Tip60 HAT activity in neuronal development with a focus on disease, we have generated fly lines that produce varying levels of both Tip60 HAT activity and the Alzheimer's Disease related amyloid precursor protein (APP). Ubiquitous and neuronal targeted expression of these constructs reveals a genetic interaction between Tip60 and APP in neuronal development and specifically in the regulation of apoptosis in the fly brain. This research should shed light on epigenetic based mechanisms underlying neuronal gene misregulation and neurodegeneration in human neurological disorders.
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Details
- Title
- Tip60 and APP genetically interact to promote apoptosis-driven neurodegeneration
- Creators
- Meridith Toth Lorbeck - DU
- Contributors
- Felice Elefant (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 3418; 991014632296504721