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Genomic Interactions of the Transcription Factor VEZF1

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Genomic Interactions of the Transcription Factor VEZF1 Low, Carolyn M. (2013) Genomic interactions of the transcription factor VEZF1. PhD thesis. https://theses.gla.ac.uk/5078/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Genomic interactions of the transcription factor VEZF1 Thesis submitted for the degree of Doctor of Philosophy By Carolyn M. Low Institute of Cancer Sciences College of Medical, Veterinary and Life Sciences University of Glasgow September 2013 Abstract VEZF1 is a highly conserved vertebrate transcription factor. VEZF1 binding sites have been reported to function in gene promoter activation, insulator barrier activity and protection from de novo DNA methylation. This study aims to identify VEZF1 binding sites across the human genome and to develop a better understanding of the gene regulatory processes mediated by VEZF1. ChIP-seq was used to map VEZF1 binding sites across the genome of human erythroid cells. A strong association of VEZF1 with regulatory elements was discovered, particularly at active promoters and enhancers. Investigation of the binding specificity of VEZF1 resulted in the identification of consensus DNA recognition sequences. VEZF1 has a preference for binding to homopolymeric dG motifs in vitro and in vivo. However, VEZF1 has a broader specificity for previously undiscovered degenerate motifs in vivo. VEZF1 interacts with degenerate motifs at erythroid-specific gene regulatory elements, and evidence is presented which indicates that VEZF1 co-operates with erythroid-specific transcription factors to enable binding to these elements in vivo. Investigation of erythroid-specific regulatory elements in vivo in embryonic chicken erythrocytes, revealed a correlation between VEZF1-enrichment of promoter elements, DNA methylation status, and expression of the β-globin genes. These analyses also indicate a role for VEZF1 in mediating DNA demethylation. The findings presented in this thesis provide an insight into the regulatory functions of VEZF1 and indicate a role for VEZF1 in the activation of gene expression. 3 Table of Contents Title page ............................................................................................................ 1 Abstract ............................................................................................................... 2 Table of contents ................................................................................................. 3 List of figures ....................................................................................................... 8 List of tables ........................................................................................................ 11 Acknowledgment ................................................................................................. 12 Author’s declaration ............................................................................................ 13 Chapter 1 Introduction ...................................................................................... 14 1.1 Basic chromatin structure................................................................................... 14 1.2 Structure of the eukaryotic genome .................................................................. 15 1.2.1 Coding and non-coding regions ............................................................ 15 1.2.2 Regulatory elements ............................................................................ 16 1.2.2.1 The core promoter .................................................................... 16 1.2.2.2 Proximal promoter elements ................................................... 17 1.2.2.3 Enhancer elements ................................................................... 17 1.2.2.4 Silencer elements ..................................................................... 18 1.3 Chromatin and transcriptional regulation .......................................................... 18 1.3.1 Chromatin domains .............................................................................. 18 1.3.2 Nucleosome density and positioning ................................................... 19 1.3.3 Chromatin remodelling complexes ...................................................... 21 1.3.4 Histone modifications ........................................................................... 23 1.3.4.1 Histone acetylation ................................................................... 24 1.3.4.2 Histone methylation ................................................................. 25 1.3.5 Histone variants .................................................................................... 26 1.3.6 Histone cross-talk ................................................................................. 28 1.3.7 Histone modifications at regulatory elements ..................................... 28 1.3.8 General transcription factors ............................................................... 29 1.3.9 Transcription factors and co-operativity .............................................. 30 1.4 DNA methylation ................................................................................................ 30 1.4.1 Cytosine methylation ........................................................................... 30 1.4.2 CpG-containing DNA elements ............................................................. 31 1.4.3 Directing DNA methylation .................................................................. 31 1.4.4 Protection from DNA methylation ....................................................... 32 1.4.5 DNA demethylation .............................................................................. 34 1.4.6 Bisulphite sequencing ........................................................................... 36 1.5 Genome-wide mapping of epigenetic modifications ......................................... 37 1.5.1 Chromatin Immunoprecipitation ......................................................... 37 1.5.1.1ChIP-chip .................................................................................... 38 1.5.1.2ChIP-seq ..................................................................................... 39 1.5.2 MeDIP ................................................................................................... 41 1.5.3 ENCODE ................................................................................................ 42 1.6 The chicken β-globin locus ................................................................................. 43 1.7 Insulators ............................................................................................................ 45 1.8 VEZF1 .................................................................................................................. 47 1.9 VEZF1 ChIP-chip .................................................................................................. 50 1.10 Methods for identifying TF binding sites and generating consensus binding sequences ........................................................................................................... 52 4 1.10.1 DNase I footprinting ............................................................................. 53 1.10.2 EMSA ..................................................................................................... 53 1.10.3 Microwell-based protein DNA-binding specificity assay ...................... 54 1.10.4 SELEX-seq .............................................................................................. 55 1.10.5 ChIP-seq ................................................................................................ 56 1.11 The K562 cell line ................................................................................................ 56 1.12 Aims and objectives of this thesis ...................................................................... 58 Chapter 2 Materials and Methods ...................................................................... 60 2.1 Cell lines .............................................................................................................. 60 2.2 Reagents ............................................................................................................. 60 2.2.1 Cell culture reagents ............................................................................. 60 2.2.2 Antibodies ............................................................................................. 60 2.2.3 Enzymes ................................................................................................ 60 2.2.4 Oligonucleotides ................................................................................... 61 2.2.5 Plasmids ................................................................................................ 61 2.2.6 Chemicals .............................................................................................. 61 2.2.7 Other molecular biology reagents .......................................................
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