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Functional Analysis of Human Enhancers Using the Zebrafish FUNCTIONAL ANALYSIS OF HUMAN ENHANCERS USING THE ZEBRAFISH EMBRYO by IRENE MIGUEL ESCALADA A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Department of Medical and Molecular Genetics School of Clinical and Experimental Medicine College of Medical and Dental Sciences The University of Birmingham June 2014 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract In the post-genomic era the availability of genome-wide datasets has revealed an unexpected complexity of transcriptional regulation. In this context, where most enhancer predictions are based on computational analyses, functional validations are lacking. This thesis investigated the utility of the transgenic zebrafish embryo as an in vivo vertebrate model to study the function of candidate human enhancers, and detect subtle changes in enhancer function caused by disease- associated variants. Our functional validations indicated that despite the evolutionary distance between human and fish, 60% of the conserved enhancers predicted by a combination of chromatin signatures, TF binding events and bidirectional transcription, lead to reporter expression that recapitulates the patterns of either zebrafish or human genes. To improve the reliability of zebrafish transgenesis, a targeted integration system mediated by PhiC31 integrase was validated for enhancer testing. I demonstrated that this method overcomes position effect variation commonly found in transposon-based assays. However, enhancer-driven expression could not be detected when I attempted to quantitate TCF7L2-associated enhancer variants, indicating the need for further studies to understand the limitations of the zebrafish model. Taken together, my results provide strong support for zebrafish as a valuable in vivo model to study the function of mammalian transcriptional regulatory elements. Acknowledgements First and foremost I would like to thank my supervisor Professor Ferenc Müller, for his constant support, enthusiasm and help throughout these years, for offering me exciting projects and for trusting me with new collaborations. I also want to thank my co-supervisor, Professor Paul Gissen for his support; and Marie Curie Actions for funding my PhD. I would like to acknowledge our collaborators Lorenzo Pasquali (IDIBAPS, Spain) and Jorge Ferrer (Imperial College, UK), with whom we have actively worked on all the pancreas-related projects for the last 3 years. Thanks to Robin Andersson and Albin Sandelin (The Bioinformatic Centre, Copenhagen University, Denmark) and the FANTOM5 Consortium for letting us be part of the enhancer-ome project. Thanks to all for sharing their extensive bioinformatic datasets and analyses, and for their enthusiasm for the zebrafish experiments. Thanks to all the members of the Marie Curie “Biology of Liver and Pancreatic Development and Disease” (BOLD) Initial Training Network for fruitful discussions and wonderful meetings. Thanks to all current and past members of the Müller lab, especially Yavor Hadzhiev and Nan Li, the best post-docs I could have asked for; thanks for being willing to help at any time (literally); Andreas Zaucker, for introducing me to the zebrafish world; Jenny Roberts, Harmeet Gill, Aliesha Griffins and Silvia Parajes for their invaluable help and for being excellent colleagues, and to all of them for being even better friends after hours. Finally, thanks to my family and friends for their daily words of encouragement. Last but certainly not least, thanks to my partner Nuno, for his constant support and love. Thanks for being my touchstone. Without all of you this PhD would not have been possible. Table of Contents Chapter One: GENERAL INTRODUCTION ................................................................................................. 1 1.1 Transcriptional regulation mediated by RNA Polymerase II: overview ........................................ 1 1.2 Cis-Regulatory Elements................................................................................................................ 3 1.2.1 Core promoters ......................................................................................................................... 3 1.2.2 Proximal promoter.................................................................................................................... 6 1.2.3 Silencers .................................................................................................................................... 7 1.2.4 Insulators .................................................................................................................................. 7 1.3 Enhancers ...................................................................................................................................... 8 1.3.1 Modularity and redundancy of enhancers ............................................................................... 9 1.3.2 Transcription factors and enhancer function ......................................................................... 11 1.3.2.1 Binding of sequence-specific TFs to enhancers .......................................................... 12 1.3.2.2 Enhancer architecture: models of TF recruitment ..................................................... 13 1.3.2.3 Pioneer factors during development .......................................................................... 15 1.3.3 Enhancer-promoter specificity .............................................................................................. 16 1.3.4 Enhancer-promoter interactions ............................................................................................ 17 1.4 Genome-wide strategies for enhancer prediction ...................................................................... 20 1.4.1 Comparative genomics as a tool for the identification of non-coding functional elements .. 21 1.4.2 Open chromatin sites as indicators of CRE regions ................................................................ 24 1.4.3 Combinatorial binding of transcription factors define enhancers ......................................... 25 1.4.4 Binding of general transcriptional co-factors: CBP/p300 mark enhancers ............................ 26 1.4.5 Histone modification marks as predictors of enhancers ........................................................ 27 1.4.6 H2AZ histone variant correlates with nucleosome-free regions ............................................ 30 1.4.7 Transcription from enhancers is pervasive and might aid in enhancer detection ................. 31 1.5 Cis-regulation and disease .......................................................................................................... 31 1.6 Zebrafish as a model organism ................................................................................................... 33 1.6.1 General characteristics ........................................................................................................... 34 1.6.2 Resources and tools available to the zebrafish community ................................................... 35 1.7 Transgenesis in zebrafish for the study of transcriptional regulation ........................................ 37 1.7.1 Zebrafish tests of human cis-regulatory elements ................................................................. 38 1.7.2 Transgenesis methods in zebrafish ......................................................................................... 39 1.7.3 Use of transposons for random integration of transgenes .................................................... 40 1.7.3.1 Sleeping Beauty .......................................................................................................... 40 1.7.3.2 Tol2 transposon .......................................................................................................... 41 1.7.4 Zebrafish as a model for studying cis-regulation of vertebrate pancreas development and function ............................................................................................................................ 42 1.7.4.1 Zebrafish shares a common pancreas structure and function with mammals .......... 42 1.7.4.2 Zebrafish pancreas development ............................................................................... 43 1.8 Aims of this thesis ....................................................................................................................... 45 Chapter Two: MATERIAL AND METHODS ............................................................................................. 46 2.1 Materials ..................................................................................................................................... 46 2.1.1 Antibiotics ............................................................................................................................... 46 2.1.2 Bacterial strains .....................................................................................................................
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