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Nanog-Regulated Histone Demethylation in Embryonic Stem Cell Identity

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Nanog-Regulated Histone Demethylation in Embryonic Stem Cell Identity Nanog-regulated Histone Demethylation in Embryonic Stem Cell Identity By Liangqi Xie A DISSERTATION Presented to the Department of Cell & Developmental Biology and the Oregon Health & Science University School of Medicine in partial fulfillment of the requirement for the degree of Doctor of Philosophy April 2012 TABLE OF CONTENTS Table of Contents .......................................................................................................... ii List of Figures and Tables ........................................................................................... iv List of Abbreviations .................................................................................................... vi Acknowledgements .................................................................................................... viii Abstract .......................................................................................................................... x Chapter One: Introduction ............................................................................................ 1 A Brief History of Embryonic Stem Cell Research ........................................................ 2 Pluripotent Stem Cell Characteristics ............................................................................ 4 Signaling Pathways that Regulate Pluripotent Stem Cells ............................................ 8 Genetic Network of Core Pluripotency Transcription Factors ...................................... 10 Epigenetic Mechanisms Governing Pluripotent Stem Cells ......................................... 13 Nanog Connects Genetic and Epigenetic Programs for ESC Identity ......................... 15 KDM5 Family of Histone Demethylases ...................................................................... 21 Chapter Two: KDM5B Regulates Embryonic Stem Cell Self-Renewal by Repressing Cryptic Intragenic Transcription ................................................................................ 34 Abstract ..................................................................................................................... 36 Introduction ................................................................................................................. 37 Results ....................................................................................................................... 39 Discussion .................................................................................................................. 48 Acknowledgements .................................................................................................... 53 Figure and Figure legends .......................................................................................... 54 Methods ..................................................................................................................... 76 ii Chapter Three: KDM5B, an Epigenetic Module Regulating Embryonic Stem Cell Pluripotency................................................................................................................. 81 Abstract ..................................................................................................................... 83 Introduction ................................................................................................................. 84 Results ....................................................................................................................... 86 Discussion .................................................................................................................. 97 Acknowledgements .................................................................................................. 101 Figure and Figure legends ........................................................................................ 102 Methods ................................................................................................................... 126 Chapter Four: Summary, Discussion and Conclusion .......................................... 133 Summary .................................................................................................................. 134 Discussion…………………………………………………………………………………...139 Conclusion................................................................................................................ 155 Appendices ................................................................................................................ 156 Figures .................................................................................................................... 156 Contribution to Figures ............................................................................................. 161 References ................................................................................................................. 162 iii LIST OF FIGURES AND TABLES Figure 1.1: Origin of pluripotent stem cells at different stages of the mouse embryonic development .................................................................................................. 5 Figure 1.2: A complex signaling network regulating the pluripotent state ........................ 8 Figure 1.3: Flow chart of functional genomics approaches to interrogate Nanog- regulated epigenetic mechanisms towards ESC naïve pluripotency............ 17 Figure 1.4: Biochemical mechanisms of LSD1-mediated histone demethylation………21 Figure 1.5: Biochemical mechanisms of JmjC domain-containing histone lysine demethylases (KDMs) ................................................................................ 22 Figure 1.6: Domain architecture comparison of KDM5/JARID family histone demethylase proteins .................................................................................. 23 Figure 1.7: De novo generation of phylogenetic relationships among KDM5/JARID1 family members from model organisms ...................................................... 24 Figure 1.8: Structural analysis of the catalytic JmjC domain ........................................ 26 Table 1.1: List of Nanog-regulated chromatin modulator genes .................................. 19 Table 1.2: A comparison between Kdm5b and Nanog homozygous mutant embryos. .. 31 Figure 2.1: Kdm5b is a Nanog and Oct4 target and critical for ESC self-renewal .......... 54 Figure 2.2: An unexpected role for KDM5B in transcriptional activation ........................ 56 Figure 2.3: KDM5B removes local domains of intragenic H3K4me3 ............................. 58 Figure 2.4: H3K36me3 recruits KDM5B to transcriptionally active intragenic regions ... 60 Figure 2.5: MRG15 mediates recruitment of KDM5B .................................................... 62 Figure 2.6: KDM5B safeguards transcriptional elongation by repressing cryptic transcription ................................................................................................ 64 Supplemental Figure 2.1-2.10:.................................................................................. 66-75 Figure 3.1: Functional genomics assays identify novel Nanog-regulated chromatin modulators regulating ESC identity ........................................................... 102 Figure 3.2: Kdm5b is highly enriched in pluripotent cells and tissues .......................... 104 Figure 3.3: Kdm5b expression maintains ESC self-renewal in the absence of LIF……106 iv Figure 3.4: Kdm5b supports ESCs pluripotency following long-term LIF-withdrawal culture.......................................................................................................108 Figure 3.5: Kdm5b is downstream effector of Nanog .................................................. 110 Figure 3.6: Cell cycle and DNA synthesis pathways mediate KDM5B-regulated ESC self-renewal .............................................................................................. 112 Figure 3.7: Characterizing the KDM5B demethylase complex .................................... 114 Supplemental Figure 3.1-3.5: ............................................................................... 116-125 Figure 4.1: Model of KDM5B in regulating naïve pluripotent state ............................... 155 Appendix Figure 1 ....................................................................................................... 156 Appendix Figure 2 ....................................................................................................... 157 Appendix Figure 3 ....................................................................................................... 158 Appendix Figure 4 ....................................................................................................... 159 Appendix Figure 5…………………………………………………………………………….160 v LIST OF ABBREVIATIONS AML Acute myeloid leukemia AP Alkaline phosphatase ChIP Chromatin immunoprecipitation ChIP-Seq Chromatin immunoprecipitation and high-throughput sequencing DRB 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole E5B E14Tg2a ESCs stably expressing Kdm5b transgene ECC Embryonic carcinoma cell EGC Embryonic germ cell EpiSC Epiblast stem cell ESC Embryonic stem cell FAD Reduced flavin adenine dinucleotide GRO-Seq Genome-wide nuclear run-on and high-throughput sequencing H3K4me3 Histone 3 Lysine 4 tri-methylation H3K4me36 Histone 3 Lysine 36 tri-methylation HAT Histone acetyltransferase HDAC Histone deacetylase HMT Histone methyltransferase ICM Inner cell mass iPSC Induced pluripotent stem cell JHDM JmjC-domain-containing histone demethylases JmjC Jumonji C vi Kdm5b Lysine
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