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The Mef2b Regulatory Network

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The Mef2b Regulatory Network THE MEF2B REGULATORY NETWORK by Julia Pon B.Sc., The University of Alberta, 2010 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Genome Science and Technology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2015 © Julia Pon, 2015 Abstract Myocyte enhancer factor 2B (MEF2B) is a transcription factor with somatic mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The recurrence of these mutations indicates that they may drive lymphoma development. However, inferring the mechanisms by which they may drive lymphoma development was complicated by our limited understanding of MEF2B’s normal functions. To expand our understanding of the cellular activities of wildtype and mutant MEF2B, I developed and addressed two hypotheses: (1) identifying genes regulated by wildtype MEF2B will allow identification of cellular phenotypes affected by MEF2B activity and (2) contrasting the DNA binding sites, effects on gene expression and effects on cellular phenotypes of mutant and wildtype MEF2B will indicate mechanisms through which MEF2B mutations may contribute to lymphoma development. To address these hypotheses, I first identified genome-wide MEF2B binding sites and transcriptome-wide gene expression changes mediated by MEF2B. Using these data I identified and validated novel MEF2B target genes. I found that target genes of MEF2B included the cancer genes MYC, TGFB1, CARD11, NDRG1, RHOB, BCL2 and JUN. The identification of target genes led to findings that MEF2B promotes expression of mesenchymal markers, promotes HEK293A cell migration, and inhibits DLBCL cell chemotaxis. I then investigated how K4E, Y69H and D83V mutations change MEF2B’s activity. I found that K4E, Y69H and D83V mutations decreased MEF2B’s capacity to promote gene expression in both HEK293A and DLBCL cells. These mutations also reduced MEF2B’s capacity to alter HEK293A and DLBCL cell movement. Overall, these data support the concept that MEF2B mutations may promote lymphoma development by reducing expression of MEF2B target genes that would otherwise function to help confine germinal centre B-cells to germinal centres. My research demonstrates how observations from genome-scale data can aid in the functional characterization of candidate driver mutations. Moreover, my work provides a unique resource for exploring the role of MEF2B in cell biology. I map for the first time the MEF2B regulome, demonstrating connections between a relatively understudied transcription factor and genes significant to oncogenesis. ii Preface Portions of Chapter 1 have been published: J. Pon, M.A. Marra. Driver and Passenger Mutations in Cancer. Annu. Rev. Pathology: Mechanisms of Disease. 10:25-50, 2014. © by Annual Reviews, http://www.annualreviews.org. I wrote most of the text for this review with guidance from M.A. Marra. Figure 1.5 was produced by Jianghong An. Portions of Chapters 2-5 have been accepted for publication pending formatting: J.R. Pon, J. Wong, S. Saberi, O. Alder, M. Moksa, S.W.G. Cheng, G.B. Morin, P.A. Hoodless, M. Hirst, M.A. Marra. MEF2B Mutations in Non-Hodgkin Lymphoma Dysregulate Cell Migration by Decreasing Transcriptional Activation of MEF2B Target Genes. Nature Communications. I designed and performed the research, analyzed and interpreted data, and drafted the manuscript. J.W. produced data in Figures 5.1b and 5.2b and optimized protein detection. S.S. ran MACS2 peak calling and IDR analysis for ChIP-seq data shown in Figure 3.9b. O.A. optimized conditions for gel shift assays. M.M. performed ChIP library construction. RNA-seq library construction, sequencing, alignment of sequence data, and the production of quality control metrics was performed by staff of the British Columbia Genome Sciences Centre. S.W.G.C. and G.B.M. provided advice on gel shift assays and purification of MEF2B-V5 expressed in E. coli. P.A.H. provided advice on gel shift assays and contributed to research design. M.H. advised and co-ordinated ChIP-seq data collection. M.A.M. conceived of the research questions and participated in research design and data interpretation. Dr. Suganthi Chittaranjan also provided guidance on experimental design and data presentation. Dr. Ryan Morin identified the MEF2C mutations reported in Table 1.2. Data in Figure 4.2 and the empty vector cell line was produced by Katie O’Brien, and data in Figure 5.1d was produced by Annie Moradian, Jessica Tamura- Wells and Marlo Firme. iii Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables ................................................................................................................................ ix List of Figures ................................................................................................................................ x List of Abbreviations ................................................................................................................. xiii Acknowledgements ..................................................................................................................... xv Dedication .................................................................................................................................. xvii Chapter 1: Transcriptional Dysregulation in Cancer and the Potential Role of MEF2B Mutations as Drivers of Non-Hodgkin Lymphoma ................................................................... 1 1.1 Introduction ........................................................................................................................... 1 1.2 Cancer biology ...................................................................................................................... 1 1.3 Regulation of transcription by chromatin structure…………………………………………3 1.4 Non-Hodgkin lymphomas ..................................................................................................... 5 1.4.1 Clinical characteristics of DLBCL, FL and MCL .......................................................... 6 1.4.2 The cellular origin of DLBCL, FL and MCL................................................................. 7 1.4.3 Driver genes of FL, DLBCL and MCL .......................................................................... 9 1.5 Technologies and model systems for characterizing transcription factors ......................... 10 1.5.1 Technologies for identifying transcription factor target genes .................................... 10 1.5.2 Distinguishing direct and indirect target genes ............................................................ 12 1.5.3 Target gene identification as a means of characterizing how transcription factor filller th mutations may contribute to lymphoma development .......................................................... 13 1.5.4 Model systems for examining cancer gene function .................................................... 14 1.6 MEF2 family proteins ......................................................................................................... 16 1.6.1 Roles of MEF2 proteins in vertebrate organisms ......................................................... 16 iv 1.6.2 Expression patterns of MEF2B .................................................................................... 17 1.6.3 Target genes of MEF2 family proteins ........................................................................ 18 1.6.4 Functions of the MADS and MEF2 domains in MEF2 proteins ................................. 19 1.6.5 Functions of the transactivation domains of MEF2 proteins ....................................... 22 1.7 Roles of MEF2 family proteins in human disease .............................................................. 23 1.7.1 MEF2B may act as an oncogene in some types of carcinoma ..................................... 24 1.7.2 MEF2B may act as a tumor suppressor in some types of non-Hodgkin lymphoma .... 24 1.8 Thesis roadmap and chapter summaries.............................................................................. 28 Chapter 2: Materials and Methods ........................................................................................... 40 2.1 Production of stably transfected HEK293A cell lines ........................................................ 40 2.2 Production of stably transduced DoHH2 cells .................................................................... 40 2.3 Cell culture and treatments .................................................................................................. 41 2.4 MEF2-dependent luciferase reporter assay ......................................................................... 41 2.5 Expression microarrays and qRT-PCR validation .............................................................. 42 2.6 RNA-seq library construction ............................................................................................. 43 2.7 Differential expression analysis using HEK293A RNA-seq data ....................................... 44 2.8 Chromatin immunoprecipitation (ChIP) for sequencing
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