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Methods and Mechanisms of DNA Methylation in Development and Disease Maximiliaan Schillebeeckx Washington University in St

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Methods and Mechanisms of DNA Methylation in Development and Disease Maximiliaan Schillebeeckx Washington University in St Washington University in St. Louis Washington University Open Scholarship All Theses and Dissertations (ETDs) Summer 9-1-2014 Methods and Mechanisms of DNA Methylation in Development and Disease Maximiliaan Schillebeeckx Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/etd Recommended Citation Schillebeeckx, Maximiliaan, "Methods and Mechanisms of DNA Methylation in Development and Disease" (2014). All Theses and Dissertations (ETDs). 1343. https://openscholarship.wustl.edu/etd/1343 This Dissertation is brought to you for free and open access by Washington University Open Scholarship. It has been accepted for inclusion in All Theses and Dissertations (ETDs) by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology & Biomedical Sciences Molecular Genetics & Genomics Dissertation Examination Committee: Robi Mitra, Chair James Huettner Stephen Johnson Shelly Sakiyama-Elbert Ting Wang David Wilson Methods and Mechanisms of DNA methylation in Development and Disease By Maximiliaan A Schillebeeckx A dissertation presented to the Graduate School of Arts and Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2014 St. Louis, Missouri TABLE OF CONTENTS LIST OF FIGURES ..................................................................................................................................... iv LIST OF TABLES ........................................................................................................................................ v ACKNOWLEDGEMENTS .......................................................................................................................... vi ABSTRACT OF THE DISSERTATION ....................................................................................................... x CHAPTER 1: INTRODUCTION ................................................................................................................... 1 OVERVIEW .............................................................................................................................................. 1 DNA METHYLTRANSFERASES CATALYZE THE METHYLATION OF CYTOSINE RESIDUES .......... 2 DNA METHYLATION IS IMPORTANT FOR MAINTAINING CELLULAR IDENTITY .............................. 4 DNA METHYLATION AS A MECHANSIM OF STABLE GENE SILENCING ........................................... 6 DNA METHYLATION AND NEURONAL DEVELOPMENT AND FUNCTION ......................................... 8 DNA METHYLATION IN HUMAN HEALTH ........................................................................................... 11 Cancer ................................................................................................................................................ 11 Neurological Diseases ........................................................................................................................ 13 TECHNOLOGICAL CHALLENGES AND LIMITATIONS FOR MAPPING DNA METHYLATION .......... 15 Genome-wide approaches ................................................................................................................. 16 Locus-specific approaches ................................................................................................................. 17 SCOPE OF THESIS WORK ................................................................................................................... 19 CHAPTER 2: LASER CAPTURE MICRODISSECTION-REDUCED REPRESENTATION BISULFITE SEQUENCING (LCM-RRBS) MAPS CHANGES IN DNA METHYLATION ASSOCIATED WITH GONADECTOMY-INDUCED ADRENOCORTICAL NEOPLASIA IN THE MOUSE ................................ 22 ABSTRACT ............................................................................................................................................ 22 INTRODUCTION .................................................................................................................................... 23 RESULTS ............................................................................................................................................... 25 LCM-RRBS ......................................................................................................................................... 25 LCM-RRBS accurately measures genome-wide DNA methylation of fresh frozen and formalin-fixed paraffin-embedded samples ............................................................................................................... 26 LCM-RRBS is robust across fresh frozen and formalin-fixed paraffin-embedded laser capture microdissected samples ..................................................................................................................... 27 Evaluation of PCR Bias ...................................................................................................................... 28 Analysis of GDX-induced adrenocortical neoplasia in the mouse using LCM-RRBS ......................... 28 DISCUSSION ......................................................................................................................................... 29 ACKNOWLEDGEMENTS ...................................................................................................................... 31 AUTHOR CONTRIBUTIONS ................................................................................................................. 32 MATERIALS AND METHODS ............................................................................................................... 33 Experimental mice .............................................................................................................................. 33 DNA extraction .................................................................................................................................... 33 Laser Capture Microdissection ........................................................................................................... 33 RRBS and LCM-RRBS ....................................................................................................................... 34 Bisulfite-specific PCR ......................................................................................................................... 35 Sequence alignment and methylation calling ..................................................................................... 36 Genomic feature annotation and statistical analysis .......................................................................... 36 Data Release ...................................................................................................................................... 37 SUPPLEMENTARY FIGURES AND TABLES ....................................................................................... 44 CHAPTER 3: NOVEL MARKERS OF GONADECTOMY-INDUCED ADRENOCROTICAL NEOPLASIA IN THE MOUSE AND FERRET ................................................................................................................. 51 ABSTRACT ............................................................................................................................................ 51 INTRODUCTION .................................................................................................................................... 52 RESULTS AND DISCUSSION ............................................................................................................... 53 Genes identified as hypomethylated by genome-wide analysis are upregulated in GDX-induced adrenocortical neoplasms of the mouse ............................................................................................. 53 Locus-specific DNA methylation analysis of a fetal adrenal enhancer in GDX-induced adrenocortical neoplasms .......................................................................................................................................... 55 ii RNA expression profiling identifies novel markers of GDX-induced adrenocortical neoplasia in the mouse ................................................................................................................................................. 56 FOXL2 is a marker of adrenocortical neoplasia in gonadectomized ferrets ....................................... 58 Summary ............................................................................................................................................ 59 ACKNOWLEDGMENTS ......................................................................................................................... 60 AUTHOR CONTRIBUTIONS ................................................................................................................. 60 MATERIALS AND METHODS ............................................................................................................... 61 Experimental animals ......................................................................................................................... 61 Isolation of neoplastic and normal tissue using LCM ......................................................................... 61 Global and locus-specific DNA methylation analyses ........................................................................ 61 Microarray expression profiling ..........................................................................................................
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