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The Histone Acetyltransferase Dmel\TIP60 Is Essential for Multicellular

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The Histone Acetyltransferase Dmel\TIP60 Is Essential for Multicellular The Histone Acetyltransferase Dmel\TIP60 Is Essential for Multicellular Development in Drosophila A Thesis Submitted to the Faculty of Drexel University by Xianmin Zhu in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2007 © Copyright 2007 Xianmin Zhu. All Rights Reserved iii Dedications To my beloved parents and all my teachers. iv Acknowledgments This thesis would not have been possible without the support of many people. First of all, I would like to express profound gratitude to my advisor, Dr. Felice Elefant, for her invaluable supervision, encouragement, and useful suggestions throughout this research work. Her moral support and continuous guidance enabled me to complete my work successfully. I am also indebted to and want to thank my committee members, Dr. Joseph Bentz, Dr. Mark Lechner, Dr. Jeremy Lee, Dr. Eishi Noguchi, and Dr. Peter Oelkers, for their kindest guidance and support. I would gratefully thank the department head, Dr. Mary K Howett, for her encouragement and consideration. And finally, I want to thank numerous friends in Drexel University who endured this long process with me, always offering support and love. v Table of Contents Dedications....................................................................................................................... iii Acknowledgments............................................................................................................iv Abstract........................................................................................................................... xii Chapter1: Background ....................................................................................................1 Chromatin packaging and epigenetic regulation .........................................................1 Epigenetic regulation during development..................................................................4 Dosage compensation.............................................................................................5 X inactivation in mammalian systems.............................................................5 Dosage compensation in Drosophila ..............................................................7 Position effect variegation (PEV)..........................................................................9 Genomic impriting ...............................................................................................10 Polycomb group / Trithorax group ......................................................................12 Lineage restriction................................................................................................17 Nervous system..............................................................................................17 Muscle ............................................................................................................21 Histone acetylation and histone acetyltransferases ...................................................27 TIP60 cellular function...............................................................................................29 HAT catalysis.......................................................................................................31 TIP60 complex .....................................................................................................32 vi TIP60 localization ................................................................................................34 TIP60 cellular function ........................................................................................35 Nuclear hormone receptor and prostate cancer.............................................37 Amyloid-β precursor protein and Alzheimer’s disease ................................38 DNA damage..................................................................................................41 ATM.........................................................................................................41 p53............................................................................................................43 Cell progression, cancer.................................................................................45 RB.............................................................................................................45 MYC.........................................................................................................47 NF-κB.......................................................................................................49 E2F ...........................................................................................................50 TRRAP...........................................................................................................52 VHL................................................................................................................54 Conclusion ..................................................................................................................55 Chapter2: The cloning and characterization of the histone acetyltransferase human homolog Dmel\TIP60 in Drosophila melanogaster: Dmel\TIP60 is essential for multicellular development .......................................................................57 Abstract.......................................................................................................................57 Introduction.................................................................................................................58 Materials and methods................................................................................................62 vii Identification of D. melanogaster histone acetyltransferases, isolation of cDNA clones and DNA sequencing ....................................................................62 Real-time PCR analysis of staged Drosophila RNA ..........................................64 RNAi and control Dmel\TIP60 constructs ..........................................................65 Cell Culture and transfection ...............................................................................67 Semi-quantitative RT-PCR ..................................................................................68 Creation of P-element-transformed fly lines .......................................................68 Drosophila stocks and RNAi crosses...................................................................69 Results.........................................................................................................................70 Identification and characterization of two Drosophila HAT (Dmel\HAT) genes that are homologous to human HAT genes TIP60 and ELP3 ..................70 Dmel\TIP60 and Dmel\ELP3 are differentially expressed during Drosophila development......................................................................................72 Plasmid mediated Dmel\TIP60 dsRNA production in a Drosophila embryonic cell line reduces cell viability and Dmel\TIP60 mRNA levels ........74 Dmel\TIP60 is essential for Drosophila development........................................77 Targeted expression of Dmel\TIP60/RNAi in the mesoderm and muscle cells of Drosophila results in lethal muscle mutant phenotypes.........................80 Discussion...................................................................................................................82 Chapter 3: Dmel\TIP60 is required for the differentiation of a variety of specific cell and tissue types during Drosophila development...................................87 Abstract.......................................................................................................................87 Introduction.................................................................................................................88 Materials and methods................................................................................................93 viii Drosophila stocks.................................................................................................93 Creation of Dmel\TIP60/OverEX fly lines..........................................................94 Semi-quantitative RT-PCR ..................................................................................95 Viability and mutant phenotype analyses............................................................96 Immunohistochemical staining of embryos ........................................................97 Immunohistochemical staining of larval tissues .................................................98 TUNEL Assay......................................................................................................99 Results.......................................................................................................................100 An additional copy of Dmel\TIP60 rescues Dmel\TIP60/RNAi induced lethality ...............................................................................................................100 Dmel\TIP60 is required for the cell growth and differentiation during wing development ..............................................................................................103 Dmel\TIP60 is required for the development of central nervous system.........106 Dmel\TIP60 is required for muscle formation in the developing embryo .......109 Discussion.................................................................................................................111 Chapter 4: Conclusion and Future Direction
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