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Epigenetic Regulation of the Human Genome by Transposable Elements

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Epigenetic Regulation of the Human Genome by Transposable Elements EPIGENETIC REGULATION OF THE HUMAN GENOME BY TRANSPOSABLE ELEMENTS A Dissertation Presented to The Academic Faculty By Ahsan Huda In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy in Bioinformatics in the School of Biology Georgia Institute of Technology August 2010 EPIGENETIC REGULATION OF THE HUMAN GENOME BY TRANSPOSABLE ELEMENTS Approved by: Dr. I. King Jordan, Advisor Dr. John F. McDonald School of Biology School of Biology Georgia Institute of Technology Georgia Institute of Technology Dr. Leonardo Mariño-Ramírez Dr. Jung Choi NCBI/NLM/NIH School of Biology Georgia Institute of Technology Dr. Soojin Yi, School of Biology Georgia Institute of Technology Date Approved: June 25, 2010 To my mother, your life is my inspiration... ACKNOWLEDGEMENTS I am evermore thankful to my advisor Dr. I. King Jordan for his guidance, support and encouragement throughout my years as a PhD student. I am very fortunate to have him as my mentor as he is instrumental in shaping my personal and professional development. His contributions will continue to impact my life and career and for that I am forever grateful. I am also thankful to my committee members, John McDonald, Leonardo Mariño- Ramírez, Soojin Yi and Jung Choi for their continued support during my PhD career. Through my meetings and discussions with them, I have developed an appreciation for the scientific method and a thorough understanding of my field of study. I am especially grateful to my friends and colleagues, Lee Katz and Jittima Piriyapongsa for their support and presence, which brightened the atmosphere in the lab in the months and years past. I am also grateful to the other members of my lab, Andy Conley, Jianrong Wang, Daudi Jjingo and Eishita Tyagi for helpful discussions and encouragement for my research. I have immense gratitude for my friends at Georgia Tech, especially Nalini Polavarapu and Nina Schubert for their sincere love and friendship that I will cherish for years to come. I am also obliged to Gaurav Arora, Eser Kirkizlar, Anjana Varadarajan for enriching my experience at Georgia Tech in more ways than one. I am very much appreciative of my friends in Atlanta: Moid Ansari, Kamlesh Desai, Himanshu Mishra, Boby Antony, Abid Bhatti, Shameet Doshi, Shawn Lakhani, Dhana Sekar, Faisal Alam, Aditya Kar, Darly Reyes, Melvin Medina, Mark Henderson, iv Bob Fox and Lilya Matyunina who have made my years in so colorful. We have shared countless moments of laughter and sorrow and their friendship has made all the difference in my life. I am especially indebted to Bandu Koditawaku and Hussain Askree (Chenoo) for everything they have done for me. I would not have come this far without their guidance, love and support. It is beyond words to express my gratitude for my partner Vijay Jaswani, for his unwavering love and support that has enabled me to reach this milestone in my life. Last but not the least, I am grateful to my family, my brother Sohaib Huda, my sister Faria Huda, my mother Mudassir Asrar Zaidi, and my father Israr-ul-Huda, for their unconditional love that has filled my life with much happiness. v TABLE OF CONTENTS ACKNOWLEDGEMENTS............................................................................................... iv LIST OF TABLES............................................................................................................. xi LIST OF FIGURES .......................................................................................................... xii LIST OF SYMBOLS AND ABBREVIATIONS ............................................................. xv SUMMARY..................................................................................................................... xix CHAPTERS 1 – INTRODUCTION AND LITERATURE REVIEW .................................................... 1 Transposable elements and evolution............................................................................. 1 Transposable elements in the human genome ................................................................ 2 Genome defense, co-option and exaptation.................................................................... 5 Repetitive DNA and nucleosome binding ...................................................................... 7 Transposable elements and epigenetic histone modifications ........................................ 9 2 – ANALYSIS OF TRANSPOSABLE ELEMENT SEQUENCES USING CENSOR AND REPEATMASKER ................................................................................................. 15 Complementary methods .......................................................................................... 17 De novo methods....................................................................................................... 18 Class-specific methods.............................................................................................. 20 Pipeline methods....................................................................................................... 21 CENSOR................................................................................................................... 21 RepeatMasker ........................................................................................................... 23 vi 3 – EPIGENETIC REGULATION OF MAMMALIAN GENOMES BY TRANSPOSABLE ELEMENTS...................................................................................... 36 TEs and epigenetics in mammals.............................................................................. 39 Hypothesis 1: TE sequences have specific nucleosome binding properties with regulatory implications for nearby genes.................................................................. 42 Hypothesis 2: TE sequences are involved in the phasing of nucleosomes ............... 44 Hypothesis 3: TE sequences recruit epigenetic modifications to function as enhancers................................................................................................................... 46 Hypothesis 4: Epigenetic modifications at TE sequences effect the regulation of nearby genes.............................................................................................................. 49 Hypothesis 5: TEs serve as epigenetic boundary elements ...................................... 50 4 – REPETITIVE DNA ELEMENTS, NUCLEOSOME BINDING AND HUMAN GENE EXPRESSION....................................................................................................... 53 Abstract......................................................................................................................... 53 Introduction................................................................................................................... 54 Methods ........................................................................................................................ 56 Promoter sequence analysis ...................................................................................... 56 Repeat-based promoter clustering............................................................................. 58 Gene Expression Analysis ........................................................................................ 59 Probabilistic analysis of promoter repeats ................................................................ 60 Gene Ontology (GO) analysis................................................................................... 63 Statistical Analysis.................................................................................................... 63 Results and discussion .................................................................................................. 64 Repetitive DNA and nucleosome binding affinity.................................................... 64 Cross-species comparison......................................................................................... 70 TE-specific effects on nucleosome binding affinity ................................................. 72 vii Promoter repeat architecture and gene expression levels ......................................... 75 Promoter repeat architecture and tissue-specific gene co-expression....................... 77 Probabilistic analysis of promoters and gene expression ......................................... 81 Gene Ontology analysis ............................................................................................ 82 Conclusions................................................................................................................... 86 Acknowledgements....................................................................................................... 86 5 – EPIGENETIC HISTONE MODIFICATIONS OF HUMAN TRANSPOSABLE ELEMENTS: GENOME DEFENSE VERSUS EXAPTATION ..................................... 87 Abstract......................................................................................................................... 87 Introduction................................................................................................................... 89 Results and discussion .................................................................................................. 92 Characterization of TE histone modifications .......................................................... 92 Active versus repressive TE histone modifications .................................................. 97 TE ages and histone modifications ........................................................................
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