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GENOMIC IMPRINTING and X-CHROMOSOME INACTIVATION in the GRAY, SHORT-TAILED OPOSSUM, MONODELPHIS DOMESTICA a Dissertation by KORY

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GENOMIC IMPRINTING and X-CHROMOSOME INACTIVATION in the GRAY, SHORT-TAILED OPOSSUM, MONODELPHIS DOMESTICA a Dissertation by KORY GENOMIC IMPRINTING AND X-CHROMOSOME INACTIVATION IN THE GRAY, SHORT-TAILED OPOSSUM, MONODELPHIS DOMESTICA A Dissertation by KORY CHARLES DOUGLAS Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Paul B Samollow Committee Members, Scott Dindot Charles Long Keith Maggert Head of Department, Craig Coates December 2013 Major Subject: Genetics Copyright 2013 Kory Charles Douglas ABSTRACT Imprinted genes have been extensively documented in eutherian mammals and exhibit significant interspecific variation, both in the suites of genes that are imprinted and in their regulation between tissues and developmental stages. Much less is known about imprinted loci in metatherian (marsupial) mammals, wherein studies have been limited to a small number of genes imprinted in eutherians. In this dissertation, I used ChIP-seq and RNA-seq approaches to conduct the first ab initio search for imprinted autosomal genes in fibroblasts, fetal brain, and placenta of a metatherian mammal, the gray short-tailed opossum, Monodelphis domestica, and the first chromosome-wide study of paternally imprinted metatherian X chromosome inactivation. Evidence from a few genes in diverse species suggests that metatherian X- chromosome inactivation is characterized by exclusive, but incomplete (leaky), repression of genes on the paternally derived X chromosome. Herein I show that the majority of opossum X-linked genes exhibit paternally imprinted expression with 100% maternal-allele expression, whereas ~14% of genes escape inactivation, exhibiting varying levels of biallelic expression. In addition, I have shown that transcriptionally opposing histone modifications correlate strongly with opossum XCI. However, the opossum did not show an association between X-linked gene expression and promoter DNA methylation. In generating the first genome-wide profile of histone modification states for a metatherian mammal, and coupling it with in-depth gene expression analyses, I ii identified the first set of genes imprinted in a metatherian that are not imprinted in eutherian mammals and described transcriptionally opposing histone modifications and differential DNA methylation at the promoters of a subset of these genes. My findings suggest that metatherians use multiple epigenetic mechanisms to mark imprinted genes and support the concept that lineage-specific selective forces can produce sets of imprinted genes that differ between metatherian and eutherian lines. Overall, these studies furnish a comprehensive catalog of parent-of-origin expression status for both autosomal and X-linked genes in a metatherian, Monodelphis domestica, and open new avenues for illuminating the mechanisms and evolution of imprinted gene regulation in mammals generally. iii ACKNOWLEDGEMENTS I would like to thank my committee chair, Dr. Paul Samollow, and my committee members, Dr. Scott Dindot, Dr. Charles Long, and Dr. Keith Maggert for their guidance and support throughout the course of this research. I would also like to thank my many collaborators for their contributions to my work especially Madhuri Jasti as well as Dr. Andrew Clark and Dr. Xu Wang at Cornell University. Without their contributions, this work would not have been possible. I cannot thank my many colleagues at Texas A&M University enough for their willingness to celebrate the successes and help me to survive the struggles. Our many conversations and discussions have shaped me both personally and professionally, and I will always cherish our time together. Finally, I would like to thank my wife, Lauren, and son, William, for their patience, steadfastness, understanding, and love. I would also like to thank my family and friends for their unending support. iv TABLE OF CONTENTS Page ABSTRACT ..................................................................................................................... ii ACKNOWLEDGEMENTS .............................................................................................. iv TABLE OF CONTENTS ................................................................................................... v LIST OF FIGURES ......................................................................................................... vii LIST OF TABLES ............................................................................................................ ix CHAPTER I INTRODUCTION ....................................................................................... 1 1.1 Monodelphis domestica as a Model Organism ........................................................ 1 1.2 Genomic Imprinting ................................................................................................. 3 1.3 Occurrence of Imprinted Genes in Metatherian and Eutherian Mammals .............. 5 1.4 Genomic Imprinting in Other Species ..................................................................... 7 1.5 DNA Methylation and Imprinting Control .............................................................. 8 1.6 Histone Modifications and Imprinting Control ...................................................... 11 1.7 X-Chromosome Inactivation .................................................................................. 13 1.8 Specific Aims and Structure .................................................................................. 13 CHAPTER II PATERNALLY IMPRINTED X-CHROMOSOME INACTIVATION (XCI) AND ESCAPERS OF XCI ............................... 16 2.1 Introduction ............................................................................................................ 16 2.2 Results .................................................................................................................... 20 2.3 Discussion .............................................................................................................. 43 2.4 Methods ................................................................................................................. 51 CHAPTER III CHIP-SEQ IDENTIFIES THE FIRST MARSUPIAL-SPECIFIC IMRPINTED GENE ............................................................................... 54 3.1 Introduction ............................................................................................................ 54 3.2 Methods ................................................................................................................. 59 3.3 Results .................................................................................................................... 64 3.4 Discussion .............................................................................................................. 73 3.5 Conclusion ............................................................................................................. 79 v Page CHAPTER IV GENOMIC IMPRPINTING IN FETAL BRAIN AND EXTRA-EMBRYONIC MEMBRANES ............................................... 80 4.1 Introduction ............................................................................................................ 80 4.2 Results .................................................................................................................... 82 4.3 Conclusions and Future Work ............................................................................... 93 CHAPTER V EXTENDED METHODS ........................................................................ 97 5.1 Chapter II Extended Methods ................................................................................ 97 5.2 Chapter III Extended Methods ............................................................................. 109 CHAPTER VI CONCLUSIONS .................................................................................. 111 6.1 Detection of Autosomal and X-Linked Candidate-Imprinted Genes in M. domestica by Epigenetic Profiling ....................................................................... 111 6.2 Chromosome-Wide Characterization of Paternally Imprinted X-Chromosome Inactivation in M. domestica ............................................................................... 113 6.3 Autosomal Imprinted Genes in M. domestica ...................................................... 116 6.4 Conclusion ........................................................................................................... 121 REFERENCES .............................................................................................................. 122 APPENDIX A SUPPLEMENTAL FIGURES .............................................................. 139 APPENDIX B SUPPLEMENTAL TABLES ................................................................ 158 vi LIST OF FIGURES Page Figure 1. Locations and allelic expression profiles of genes on the opossum X chromosome in fetal brain and extra-embryonic membranes (EEM) ............ 21 Figure 2. Pyrosequencing analysis of maternally vs. paternally derived allele expression ratios for 24 imprinted X-inactivation escaper genes from in opossum female fetal brain and EEM ............................................................ 24 Figure 3. Comparison of paternal X-linked gene expression percentage and female/male expression ratios. ....................................................................... 28 Figure 4. Depletion of H3K27me3 marks at opossum XCI escaper genes ................... 31 Figure 5. Histone modification is correlated with maternal vs. paternal-allele expression
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