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Hippocampal Epigenetic Changes in a Mouse Model of Fetal Alcohol Spectrum Disorders

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Hippocampal Epigenetic Changes in a Mouse Model of Fetal Alcohol Spectrum Disorders Western University Scholarship@Western Electronic Thesis and Dissertation Repository 4-20-2017 12:00 AM Hippocampal epigenetic changes in a mouse model of Fetal Alcohol Spectrum Disorders Eric J. Chater-Diehl The University of Western Ontario Supervisor Shiva M. Singh The University of Western Ontario Graduate Program in Biology A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Eric J. Chater-Diehl 2017 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Genomics Commons Recommended Citation Chater-Diehl, Eric J., "Hippocampal epigenetic changes in a mouse model of Fetal Alcohol Spectrum Disorders" (2017). Electronic Thesis and Dissertation Repository. 4479. https://ir.lib.uwo.ca/etd/4479 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Fetal alcohol spectrum disorders (FASD) refers to the neurological, developmental, and behavioural abnormalities arising from in utero ethanol exposure. These abnormities included attention deficit, anxiety, and learning and memory impairment persisting into adulthood. The molecular mechanisms of such persistent behavioural changes remain unknown and are an area of intense research. In this thesis, mice were exposed to ethanol during the third trimester equivalent, the peak of synaptic development. Following this exposure, genome-wide epigenetic and gene expression and changes in the hippocampus were assessed in adult (70 day old) mice. In the first experiment, genome-wide trimethylation of histone H3 at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) were assessed using chromatin immunoprecipitation (ChIP) microarray (ChIP-chip). Cell-cell signalling genes were enriched for changes in both methylations. It included the protocadherin (Pcdh) genes, which confer neuronal identity and may be important for synaptic development. Changes in methylation also occurred at imprinted genes and lipid-metabolism genes The second experiment assessed DNA methylation using methylated DNA immunoprecipitation (MeDIP) microarray (MeDIP-chip). The screen identified genes involved in peroxisome biogenesis, which metabolize lipids and generate free-radicals. This was also true when the histone and DNA methylation changes were considered together. Combined analysis of affected genes from each experiment implicated free-radical scavenging genes. Identification of this novel interplay between epigenetic and oxidative stress genes may provide insight into diagnostic or therapeutic interventions. In general, the results support a role of epigenetic mechanisms in long-term FASD phenotypes. Finally, the third experiment examined gene expression and miRNA microarrays identified 59 and 60 differentially expressed genes and miRNAs between ethanol-exposed and control mice. These genes primarily affect free radical scavenging genes. Differential expression of five genes in this pathway was confirmed with droplet digital PCR (ddPCR), including the transcription factor Tcf7l2 and the apoptosis regulator Casp3. The affected genes also included other oxidative stress proteins, olfactory receptors, and biosynthetic enzymes that may contribute to FASD-related abnormalities. I Keywords Prenatal, Binge, Fetal Alcohol Spectrum Disorders (FASD), Gene expression, Epigenetics, Histone, DNA methylation, Synaptogenesis, Hippocampus II Co-Authorship Statement The contents of this thesis contain modified portions of published manuscripts, for which I (E.J.C.D.) was primary author. I performed, or assisted with all aspects manuscript preparation, including experimental design, sample collection and preparation, experimental execution, data analysis, and writing all alongside Dr. Shiva M. Singh. Chapters 2 and 4 contain material from a published manuscript entitled “Alteration of gene expression, DNA methylation, and histone methylation in free radical scavenging networks in adult mouse hippocampus following fetal alcohol exposure”. This manuscript was published in PLoS One on May 2, 2016. It is co-authored by Benjamin I. Laufer, Christina A. Castellani, Bonnie L. Alberry, and Shiva M. Singh. E.J.C.D. raised the mice, and isolated tissue, E.J.C.D., B.I.L., C.A.C, and B.L.A. performed experiments and data analysis, E.J.C.D. and S.M.S. wrote the manuscript. This manuscript was published under an open access CC-BY 3.0 license. Chapter 3 contains material from a published review article entitled “Changes to histone modifications following prenatal alcohol exposure: An emerging picture”. This review was published in Alcohol on February 4, 2017. It is coauthored by Benjamin I. Laufer and Shiva M. Singh. The content of the review was conceived by E.J.C.D., who also performed the literature review, generated images, and wrote the review. B.I.L. and S.M.S. provided creative input as well as writing and editing. This manuscript was published under a CC-BY-NC-ND 4.0 license and thus permission to reprinted images and modified text in this thesis was obtained from the publisher, which is provided in Appendix I. III Acknowledgments I would like to acknowledge my supervisor, Dr. Shiva Singh for his guidance and mentorship through my PhD studies. He has provided an ideal environment to foster my growth and development as a researcher. He has instilled in me a life-long interest in human epigenetics I look forward to pursuing. I would also like to acknowledge all the members of my laboratory past and present for their assistance and training. I am particularly grateful to Dr. Benjamin Laufer, Dr. Christina Castellani, Dr. Katarzyna Mantha, Bonnie Alberry, Dr. Melkaye Melka, Aniruddho Chokroborty-Hoque, and Randa Stringer for their support. I am appreciative of my advisors Dr. Kathleen Hill and Dr. Jim Karygiannis for their guidance throughout my graduate studies. I would also like to thank David Carter from the London Regional Genomics Centre for his assistance with the expression microarrays and data analysis. I am grateful to the team at ArrayStar Inc. for their services in performing the histone and DNA methylation microarrays. I am appreciative of EpigenDx Inc. for their services in performing the sodium bisulfite pyrosequencing. I also am grateful to the animal care and veterinary services staff at Western University for their mouse care. My family has been instrumental in my successes, especially the completion of this thesis. I am exceptionally grateful to my husband, Matthew Chater. The years of this thesis were also years of exceptional personal growth and challenge for us, including our marriage and adoption of our children. His support through my professional and personal growth have been invaluable. I am extremely grateful to my parents, Hilary Montgomery and Brian Diehl for their fervent support of my educational achievement for as long as I can remember; they made my PhD studies possible in more ways than one. I am also appreciative of my step father Richard Pumaren, my sisters, Jasmine Pumaren and Sarah Diehl, and my in-laws Ester, Paul, and Lindsay Chater for their support. I am appreciative of the personal and academic support of my friends Susan Eitutis, Carlee White, and Lauren Kolecki. Finally, I would like to thank all the faculty, administrators, and staff of the Department of Biology at the University of Western Ontario who have provided support for me over nearly a decade. IV Funding Acknowledgments This work was supported though grants from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Institutes of Health Research (CIHR). I also acknowledge my personal funding by NSERC through the Canada Graduate Scholarship-Masters (CGS M) and the Canada Graduate Scholarship-Doctorial (CGS D) awards as well as through by government of Ontario through the Ontario Graduate Scholarship (OGS). V Table of Contents Abstract .............................................................................................................................. I Keywords ......................................................................................................................... II Co-Authorship Statement ........................................................................................... III Acknowledgments........................................................................................................ IV Funding Acknowledgments ........................................................................................ V Table of Contents ......................................................................................................... VI List of Tables .................................................................................................................. X List of Figures ............................................................................................................... XI List of Appendices .................................................................................................... XIII List of Abbreviations ................................................................................................ XIV Introduction ................................................................................................. 1 Fetal Alcohol Spectrum Disorders (FASD) ............................................................ 1 1.1.1 A Limited
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