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Insights Into in Vivo Transcription Factor Targeting Through Studies of the Archetypal Zinc Finger Protein

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Insights Into in Vivo Transcription Factor Targeting Through Studies of the Archetypal Zinc Finger Protein Insights into in vivo transcription factor targeting through studies of the archetypal zinc finger protein KLF3. Jon Burdach A thesis submitted for the degree of Doctor of Philosophy Biochemistry and molecular genetics School of Biotechnology and Biomolecular Sciences University of New South Wales May 2013 Originality statement 'I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.' Signed ·· ~············· · ····· ··· ······HH H Date .... ~/1-lcP.!'f ...... .... ... ...... ......... ... ...... Table of Contents Acknowledgements ........................................................................................................................ i Publications arising from this thesis ............................................................................................. ii Journal articles .............................................................................................................................. ii Conference abstracts ..................................................................................................................... ii Abstract ........................................................................................................................................ iii Abbreviations ............................................................................................................................... iv Chapter 1. General introduction ......................................................................................... 1 1.1. Transcription factors in gene regulation ........................................................................... 1 1.1.1. Transcription factor domain structure ....................................................................... 2 1.1.2. Transcription factor families ..................................................................................... 4 1.1.3. The role of DNA sequence in determining TF occupancy........................................ 9 1.1.4. The role of chromatin in determining TF occupancy .............................................. 11 1.1.5. The role of cofactors and cobinding in determining TF occupancy ....................... 18 1.2. Krüppel-like factors ........................................................................................................ 23 1.2.1. DNA binding by KLFs ............................................................................................ 25 1.2.2. KLF3 ....................................................................................................................... 28 1.3. Aims of this thesis ........................................................................................................... 31 Chapter 2. Materials and methods .................................................................................... 32 2.1. Materials ......................................................................................................................... 32 2.1.1. Reagents and kits .................................................................................................... 32 2.1.2. Enzymes .................................................................................................................. 32 2.1.3. Cell lines ................................................................................................................. 33 2.1.4. Antibodies ............................................................................................................... 33 2.1.5. Oligonucelotides ..................................................................................................... 33 2.1.6. Vectors .................................................................................................................... 33 2.2. Laboratory methods ........................................................................................................ 34 2.2.1. General methods ..................................................................................................... 34 2.2.2. Cell culture .............................................................................................................. 34 2.2.3. Generation of retroviral and expression vectors ..................................................... 34 2.2.4. Retroviral transduction ............................................................................................ 34 2.2.5. Transient transfections for protein production ........................................................ 35 2.2.6. Nuclear extracts....................................................................................................... 35 2.2.7. SDS-PAGE ............................................................................................................. 35 2.2.8. Western blot ............................................................................................................ 35 2.2.9. Electrophoretic mobility shift assay ........................................................................ 36 2.2.10. Immunoflourescence microscopy ........................................................................... 36 2.2.11. Chromatin immunopreciptiation ............................................................................. 37 2.2.12. High-throughput sequencing ................................................................................... 37 2.2.13. Real-time PCR ........................................................................................................ 37 2.2.14. Gene expression microarrays .................................................................................. 38 2.3. Bioinformatics methods .................................................................................................. 38 2.3.1. Alignment ............................................................................................................... 38 2.3.2. Peak calling, peak overlap and genomic annotation. .............................................. 38 2.3.3. Quantification of ChIP tags. .................................................................................... 39 2.3.4. Visualization ........................................................................................................... 39 2.3.5. ENCODE data sets .................................................................................................. 39 2.3.6. Gene expression microarray analysis ...................................................................... 40 Chapter 3. Genome-wide profile of KLF3 occupancy. .................................................... 41 3.1. Introduction ..................................................................................................................... 41 3.2. Experimental model ........................................................................................................ 42 3.3. ChIP-seq .......................................................................................................................... 43 3.4. Evaluation of replicates ................................................................................................... 45 3.5. KLF3 peak characterisation ............................................................................................ 46 3.5.1. Confirmation of peaks by qPCR ............................................................................. 46 3.5.2. Distribution of KLF3 peaks across the genome ...................................................... 49 3.5.3. Peak height and sequence conservation at different genomic regions .................... 50 3.6. Overlap with differentially expression genes .................................................................. 52 3.7. RNA polymerase II and KLF3 ........................................................................................ 59 3.8. Discussion ....................................................................................................................... 63 Chapter 4. KLF3 DNA binding and chromatin state ........................................................ 68 4.1. Introduction ..................................................................................................................... 68 4.1.1. DNA binding by KLF3 ........................................................................................... 68 4.1.2. KLF3 and chromatin state ....................................................................................... 69 4.2. KLF3 DNA binding preference in vivo ........................................................................... 70 4.3. Validation of the de novo generated KLF3 consensus motif .......................................... 72 4.4. Distribution of KLF3 motifs within peaks ...................................................................... 74 4.5. Search for known motifs of other TFs ...........................................................................
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