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Rna-Mediated Programming of Active Chromatin A RNA-MEDIATED PROGRAMMING OF ACTIVE CHROMATIN A DISSERTATION SUBMITTED TO THE PROGRAM IN CANCER BIOLOGY AND THE COMMITTEE ON GRADUATE STUDIES OF STANFORD UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Yul Wonjun Yang August 2012 © 2012 by Yul Wonjun Yang. All Rights Reserved. Re-distributed by Stanford University under license with the author. This work is licensed under a Creative Commons Attribution- Noncommercial 3.0 United States License. http://creativecommons.org/licenses/by-nc/3.0/us/ This dissertation is online at: http://purl.stanford.edu/zj169pb5921 ii I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Howard Chang, Primary Adviser I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Paul Khavari I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Seung Kim I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Joanna Wysocka Approved for the Stanford University Committee on Graduate Studies. Patricia J. Gumport, Vice Provost Graduate Education This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file in University Archives. iii iv ABSTRACT Various long noncoding RNAs (lncRNAs) have been recently identified, but their functions remain unknown. To better understand the role of lncRNAs in gene activation, we have characterized a 3.76 kilobase highly conserved lncRNA, called HOTTIP, found at the 5’ distal tip of the HoxA locus. HOTTIP is required for the expression of HoxA9 to HoxA13 in human fibroblasts and chicken embryos. This region spans a linear 40 kilobases, but forms a compact three dimensional DNA structure by high throughput chromosome conformation capture. Knockdown of HOTTIP causes loss of the activating histone H3K4 trimethylation mark, as well as lost occupancy of the MLL methylase complex by chromatin immunoprecipitation coupled with tiling microarray analysis. To cause these changes, HOTTIP binds WDR5, a component of the MLL complex, to alter histone H3K4 trimethylation and gene activation. Together, the characterization of HOTTIP demonstrates an example of lncRNA-mediated epigenetic activation. A close examination of the binding interaction between HOTTIP and WDR5 has further revealed a novel pathway of lncRNA-regulated proteolysis. HOTTIP acts as a “molecular switch,” causing increased WDR5 protein levels by preventing proteasomal degradation through thermodynamic stabilization post poly-ubiquitination. Increased WDR5 deposition then causes gene activation. One HOTTIP RNA binds a single WDR5 protein through a direct RNA-protein interaction, and RNA-mediated stabilization requires a specific HOTTIP RNA domain in a long RNA context. Using a small scale alanine scanning mutagenesis screen, the HOTTIP binding interface on WDR5 has been identified as the cleft between blades 5 and 6. WDR5 mutations that abrogate lncRNA binding cannot be stabilized by HOTTIP, and are defective in gene activation, maintenance of histone H3K4 trimethylation, and embryonic stem cell self renewal. By altering protein turnover, lncRNAs may be able to regulate the temporal landscape of proteins in cells, potentially altering epigenetic states and cellular functions. v ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Howard Chang, for his mentorship, his unflappable demeanor in light of “not so good data,” and countless pages of hand drawn figures to organize experiments. Without his guidance, none of the experiments in this thesis could have occurred. In addition, I am deeply indebted to his patience and understanding for my growth as an individual. Thanks to him, I leave the Chang lab not only as a better scientist, but a more mature person. I also thank Kevin Wang, who was gracious to teach every technique to a rotation student with no prior experience in epigenetics or chromatin. I only truly realized his skill in teaching when I began working with my own rotation students. I thank my collaborators at University of Michigan, Yong Chen, Bingbing Wan, and Ming Lei, who provided vital reagents and data fundamental to my work. I also thank Kun Qu and Jiajing (Jenny) Zhang for their bioinformatics help. I also thank Karla Kirkegaard, Michel Brahic, and J. Antonio Gomez. I am also grateful to the rest of my labmates for reagents, data analysis, bench space, and/or a friendly person to talk to. I would like to thank especially Ryan Corces-Zimmerman, Ryan Flynn, and Angeline Protacio for their endless support and enthusiasm for HOTTIP, as well as Ci Chu, Paul Giresi, Tiffany Hung, Lingjie Li, Nicole Rapicavoli, Robert Spitale, Eduardo Torre, Miao Tsai, Yue Wan, Orly Wapinski, and Grace Zheng for their various contributions and much needed advice. This research was supported by the Stanford Medical Scientist Training Program, who provided both funding and much needed overall support, especially from Seung Kim, PJ Utz, Lorie Langdon, and Moira Louca. Finally, I would like to thank my parents, Sung-Chul and Young-Ok Yang, for encouraging me to do whatever I wanted. My brother, Gene Yang, for being always proud of his little brother, and somehow knowing about epigenetics as a Sociology/ Urban Studies major. I also thank my in-laws, Pete and Kelly Liberda, who always enjoy the fact that my research involves foreskin fibroblasts. Most importantly, I am forever grateful to my wife, Kristine Yang, for her love and caring for me. Without her, the work in this thesis would have never transpired. vi TABLE OF CONTENTS ABSTRACT iv ACKNOWLEDGEMENTS v TABLE OF CONTENTS vi LIST OF ILLUSTRATIONS viii CHAPTER 1: BACKGROUND 1 1.1 Significance of long noncoding RNAs 2 1.2 Introduction to epigenetics 4 1.3 Long noncoding RNAs in epigenetic silencing 5 1.4 Long noncoding RNAs in epigenetic activation 7 1.5 References 8 CHAPTER 2: A LONG NONCODING RNA MAINTAINS ACTIVE CHROMATIN TO COORDINATE HOMEOTIC GENE EXPRESSION 13 2.1 Abstract 14 2.2 Results 15 2.3 Discussion 30 2.4 Materials and Methods 31 2.5 Supplementary Figures 39 2.7 References 57 CHAPTER 3: LONG NONCODING RNA AS REGULATORY SWITCH OF PROTEIN TURNOVER 61 3.1 Abstract 62 3.2 Introduction 63 3.3 Results 66 3.4 Discussion 89 3.5 Materials and Methods 93 3.6 Supplementary Figures 101 vii 3.7 References 106 CHAPTER 4: CONCLUDING REMARKS 111 4.1 Conclusion 112 4.2 Future Directions 115 4.3 References 117 viii List of Illustrations Figure 2.1. HOTTIP is a lincRNA transcribed in distal anatomic sites. 16 Figure 2.2. HOTTIP is required for coordinate activation of 5′ HOXA genes. 20 Figure 2.3. HOTTIP RNA is required for the active chromatin state of 5′ 24 HOXA cluster. Figure 2.4. HOTTIP RNA programs active chromatin via WDR5. 27 Figure 2S1. Molecular characterization of HOTTIP. 39 Figure 2S2. Single molecule RNA-fluorescence in situ hybridization 41 (FISH) confirms low copy number of HOTTIP RNA. Figure 2S3. Lack of antisense HOTTIP RNA with HOTTIP knockdown. 42 Figure 2S4. Efficient retroviral infection in developing chick limb buds. 43 Figure 2S5. HOTTIP knockdown decreases expression of 5’ HoxA genes 44 in vivo. Figure 2S6. HOTTIP depletion causes little change to higher-order 46 chromosome configuration. Figure 2S7. ChIP-qPCR validation of HOTTIP-dependence of H3K4me3 48 occupancy at distal HOXA. Figure 2S8. Zoom-in view of Figure 2.3 highlighting HOTTIP dependence 49 of MLL1 and WDR5 localization to HOXA. Figure 2S9. HOTTIP binds stably expressed FLAG-WDR5 in HeLa cells. 50 Figure 2S10. HOTTIP overexpression does not affect distal HOXA 51 expression. Figure 2S11. Ectopic HOTTIP expression does not activate 5’HOXA genes 53 nor rescue the effects of depleting endogenous nascent HOTTIP. Figure 2S12. HOTTIPExons1-2 binds to WDR5 and acts in a dominant 55 negative manner to inhibit 5’ HOXA gene expression. Figure 2S13. Model of HOTTIP action. HOTTIP is positioned near the 56 active 5’ HOXA genes via chromosomal looping. Figure 3.1. HOTTIP RNA overexpression stabilizes exogenous 68 FLAG-WDR5. ix Figure 3.2. HOTTIP RNA thermodynamically stabilizes WDR5 and 72 does not affect ubiquitination. Figure 3.3. Full length HOTTIP RNA stabilizes WDR5 through specific 75 interactions. Figure 3.4. HOTTIP binds and stabilizes WDR5 through the same binding 78 site as RbBP5. Figure 3.5. HOTTIP binding mutations prevent HOTTIP mediated 81 stabilization of WDR5, as well as show decreased ability to activate target genes in 293T cells. Figure 3.6. WDR5 F266A mutation decreases protein stability and causes 86 defects in mouse embryonic stem cell self renewal. Figure 3.7. WDR5 F266A causes loss of self renewal genes and increased 88 expression of differentiation genes. Figure 3S1. 101 Figure 3S2. Two regions of HOTTIP bind WDR5. 102 Figure 3S3. HOTTIP bases 1953-2453 (Frag D.3) demonstrate 104 equivalent binding affinity to bases 1953-3760 (Frag D). Figure 3S4. 105 1 CHAPTER 1 Background 2 1.1 Significance of long noncoding RNAs With the conclusion of the human genome project, researchers were surprised to find that much of the genome did not appear to encode for proteins (Lander et al., 2001; Venter et al., 2001). Because proteins were deemed to be the “building blocks of life,” researchers at the time dubbed the extensive, nonttranslated regions as the “dark matter” of the genome, or more simply as “junk DNA.” Since then, many groups have been probing this untranslated “dark matter” using traditional Sanger sequencing, or the more high throughput microarray and next generation sequencing technologies (Birney et al., 2007; Cabili et al., 2011; Carninci et al., 2005; Cawley et al., 2004; Core et al., 2008; Okazaki et al., 2002; Preker et al., 2008).
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