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Are Epigenetic Mechanisms Involved in Axonal Regeneration?

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Are Epigenetic Mechanisms Involved in Axonal Regeneration? Are Epigenetic Mechanisms Involved in Axonal Regeneration? Dissertation der Mathematisch-Naturwissenschaftlichen Fakultät der Eberhard Karls Universität Tübingen zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) vorgelegt von Ricco Lindner aus Leipzig Tübingen 2013 Tag der mündlichen Qualifikation: Dekan: Prof. Dr. Wolfgang Rosenstiel 1. Berichterstatter: Prof. Dr. Philipp Kahle 2. Berichterstatter: Prof. Dr. Robert Feil Role of Epigenetic Mechanisms in Axonal Regeneration I Index of Contents I. Eidesstattliche Erklärung ....................................................................................... III II. Acknowledgment ..................................................................................................... IV III. Zusammenfassung ..................................................................................................... V IV. Executive Summary ............................................................................................... VII 1 Introduction ................................................................................................................ 2 1.1 Nerve injury and regeneration .................................................................................. 2 1.1.1 Axonal regeneration in the peripheral and central nervous system ............... 2 1.1.2 Dorsal root ganglia - a model for axonal regeneration .................................... 4 1.1.3 The extrinsic environment in the CNS inhibits axonal regeneration ............. 5 1.1.4 Intrinsic factors for successful or inhibited axonal regeneration ................... 8 1.2 Epigenetic mechanisms ............................................................................................ 11 1.2.1 DNA methylation ............................................................................................... 12 1.2.1.1 Cytosine methylation and CpG islands ............................................................... 12 1.2.1.2 DNA methyltransferases and DNA demethylation ............................................. 15 1.2.1.3 CpG-binding proteins .......................................................................................... 16 1.2.1.4 DNA methylation in genomic imprinting and embryonic development ............. 17 1.2.1.5 DNA methylation in the CNS and upon nerve injury ......................................... 18 1.2.2 Histone modifications ........................................................................................ 19 1.2.2.1 Histone acetylation, deacetylation, and modifying enzymes .............................. 21 1.2.2.2 Histone methylation, demethylation, and modifying enzymes ........................... 23 1.3 Hypothesis ................................................................................................................. 25 1.4 Project outline ........................................................................................................... 26 2 Results ........................................................................................................................ 28 2.1 Involvement of gene promoter DNA methylation in axonal regeneration .......... 28 2.1.1 Establishment of Methylated DNA immunoprecipitation (MeDIP) ............. 28 2.1.2 DNA methylation microarray analysis ............................................................ 30 2.1.3 Gene expression of DNA methyltransferases upon nerve injury .................. 35 2.1.4 Hypermethylated or hypomethylated genes ................................................... 36 2.1.5 Differentially methylated genes for both injury types ................................... 41 2.1.6 Gene expression levels of differentially methylated genes correlated with the promoter methylation status ............................................................. 43 2.1.7 Gene expression of regeneration-associated genes following nerve injury .. 44 2.1.8 CpG island analysis of regeneration-associated genes and of differentially methylated genes ........................................................................ 47 2.2 Involvement of gene promoter histone modifications in axonal regeneration .... 50 2.2.1 Gene promoter H3-K9 acetylation and dimethylation were differentially regulated upon SNA or DCA .................................................... 50 2.2.2 PCAF enhanced neurite outgrowth, RAG expression, and H3-K9 acetylation of cultured DRG or cerebellar granule neurons (CGN) ............ 52 Role of Epigenetic Mechanisms in Axonal Regeneration II 3 Discussion .................................................................................................................. 56 3.1 Summary of Results ................................................................................................. 56 3.2 Role of DNA methylation in axonal regeneration ................................................. 57 3.2.1 Experimental setup and MeDIP-chip .............................................................. 57 3.2.2 DNA methylation and expression of DNA methyltransferases ..................... 58 3.2.3 Hypermethylated and hypomethylated genes ................................................. 61 3.2.4 Differentially methylated genes ........................................................................ 64 3.2.5 Regeneration-associated genes ......................................................................... 66 3.2.6 CpG island analysis ........................................................................................... 70 3.3 Role of histone modifications in axonal regeneration ........................................... 72 4 Conclusions and Outlook ......................................................................................... 76 5 Material and Methods .............................................................................................. 79 5.1 Material ..................................................................................................................... 79 5.1.1 Buffers and Solutions, Chemicals and Reagents, Enzymes ........................... 79 5.1.2 Commercial Kits ................................................................................................ 81 5.2 Methods ..................................................................................................................... 81 5.2.1 Animal Model and Surgery .............................................................................. 81 5.2.1.1 Sciatic nerve axotomy ......................................................................................... 81 5.2.1.2 Dorsal Column Axotomy .................................................................................... 82 5.2.2 DRG dissection and sample preparation for MeDIP ..................................... 82 5.2.3 Methylated DNA Immunoprecipitation .......................................................... 82 5.2.4 Whole genome amplification ............................................................................ 84 5.2.5 DNA Methylation Microarray ......................................................................... 85 5.2.6 Quantitative Real-Time RT-PCR .................................................................... 85 5.2.6.1 RNA extraction and cDNA synthesis .................................................................. 85 5.2.6.2 Custom TaqMan Gene Expression Array ........................................................... 85 5.2.7 Promoter CGI analysis ..................................................................................... 86 5.2.8 Chromatin Immunoprecipitation .................................................................... 86 5.2.9 Primers and Design Software ........................................................................... 87 5.2.10 Primary Cell Culture, Immunocytochemistry and Analysis, Western Blot, AAV Infection, Luciferase Assay ..................................................................... 90 6 Bibliography / List of References ............................................................................ 91 7 Appendix ................................................................................................................. 108 7.1 Supplementary Tables ........................................................................................... 108 7.2 List of Abbreviations .............................................................................................. 121 7.3 List of Figures ......................................................................................................... 122 7.4 List of Tables ........................................................................................................... 123 7.5 Publications and congress presentations .............................................................. 124 7.6 Curriculum Vitae ................................................................................................... 125 Role of Epigenetic Mechanisms in Axonal Regeneration III I. Eidesstattliche Erklärung Ich erkläre hiermit, 1. dass ich bisher genau ein Promotionsverfahren begonnen aber vorzeitig abgebrochen habe (Universität Tübingen, Institut für Physiologie, von September 2006 bis April 2008, betreut durch Prof. Dr. Florian Lang und Prof. Dr. Michael Duszenko). 2. dass die vorgelegte Dissertation noch nie ganz oder teilweise als Dissertation oder sonstige Prüfungsarbeit eingereicht worden ist, allerdings bereits teilweise zur Veröffentlichung einge- reicht worden ist: “PCAF-dependent epigenetic changes promote
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