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Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks

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Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks Histone methylation by PRC2 is inhibited by active chromatin marks Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch–Naturwissenschaftlichen Fakultät der Universität Basel von Frank W. Schmitges aus Deutschland Basel, 2013 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Susan Gasser, Dr. Nicolas Thomä, Dr. Wolfgang Fischle. Basel, den 20. September 2011 Prof. Dr. Susan Gasser (Fakultätsverantwortliche) Prof. Dr. Martin Spiess (Dekan) Table of Contents Abbreviations............................................................................................................................ 6 1. Summary ............................................................................................................................... 8 2. Introduction .......................................................................................................................... 9 2.1 Chromatin ......................................................................................................................... 9 2.2 Epigenetics ........................................................................................................................ 9 2.3 Mechanisms of epigenetic regulation ............................................................................. 10 2.3.1 DNA methylation ..................................................................................................... 11 2.3.2 Histone methylation ................................................................................................. 12 2.3.3 Histone acetylation ................................................................................................... 15 2.3.4 Histone phosphorylation .......................................................................................... 16 2.3.5 Histone ubiquitination .............................................................................................. 17 2.3.6 The role of non-coding RNAs in transcriptional control ......................................... 17 2.4 Transcriptional control by polycomb and trithorax proteins .......................................... 18 2.4.1 Polycomb group complexes ..................................................................................... 19 2.4.2 Polycomb proteins in plants ..................................................................................... 21 2.4.3 Mechanisms of polycomb-mediated silencing ......................................................... 22 2.4.4 Targeting of polycomb complexes ........................................................................... 23 2.4.5 Polycomb silencing as an epigenetic memory ......................................................... 26 2.4.6 Polycomb in pluripotency and differentiation ......................................................... 27 2.5 Scope of the thesis .......................................................................................................... 29 3. Results ................................................................................................................................. 30 3.1 Histone methylation by PRC2 is inhibited by active chromatin marks .......................... 30 Summary ........................................................................................................................... 31 Introduction ....................................................................................................................... 31 Results ............................................................................................................................... 32 Discussion ......................................................................................................................... 39 Experimental Procedures .................................................................................................. 41 References ......................................................................................................................... 41 Supplemental Information ................................................................................................ 43 3 3.2 The structure of Nurf55 bound to residues 1 to 30 of histone H3- context-dependent specificity and plasticity of Nurf55 ........................................................ 58 Abstract ............................................................................................................................. 58 Introduction ....................................................................................................................... 59 Results ............................................................................................................................... 61 Discussion ......................................................................................................................... 64 Experimental Procedures .................................................................................................. 66 Figure Legends .................................................................................................................. 67 Figures ............................................................................................................................... 69 Supplemental Information ................................................................................................ 73 5. General Discussion ............................................................................................................. 75 5.1 Bistability ........................................................................................................................ 75 5.2 Components of bistable systems ..................................................................................... 75 5.3 Classical switches in cell signaling and apoptosis .......................................................... 76 5.3.1 Unidirectionality in cell biological switches ........................................................... 76 5.3.2 Thresholding in biological systems ......................................................................... 76 5.3.3 Feedback present in enzymatic complexes .............................................................. 77 5.4 Positive feedback loops in transcriptional regulation ..................................................... 77 5.5 Establishment and maintenance of heterochromatin in yeast and mammals ................. 78 5.6 Allosteric activation of chromatin modifiers .................................................................. 79 5.7 Reversing chromatin modifications ................................................................................ 80 5.8 PRC2 possesses the required circuitry making it a bistable switch ................................ 80 5.8.1 Positive feedback and inhibition in the regulation of the PRC2 complex ............... 81 5.8.2 Propagation of H3K27me3 after DNA replication .................................................. 81 5.8.3 Long-range and short-range interactions in PRC2 regulation ................................. 83 5.8.4 Formation of repressive chromatin is amplified by cooperation with demethylases ........................................................................................................................................... 83 5.8.5 A potential role for Nurf55 in further long-range interactions ................................ 84 5.8.6 Allosteric regulation allows fine-tuning of PRC2 activity ...................................... 84 5.8.7 PRC2 inhibition and bivalency - a problem for bistability? .................................... 85 5.9 Diversity of histone modifications and combinatorial readout ...................................... 85 4 5.9.1 Influence of multiple modifications on complex recruitment ................................. 86 5.9.2 Functional regulation by chromatin readers ............................................................ 87 5.9.3 The advantages of multivalent binding .................................................................... 88 5.9.4 The histone code - more than just an on/off switch ................................................. 89 5.10 Conclusion .................................................................................................................... 90 5.11 Outlook ......................................................................................................................... 91 References ............................................................................................................................... 92 Acknowledgments ................................................................................................................. 115 Curriculum vitae .................................................................................................................. 116 5 Abbreviations 5hmC 5-hydroxymethylcytosine 5mC 5-methylcytosine AEBP2 adipocyte enhancer-binding protein 2 AG AGAMOUS Ala alanine Arg arginine Ash1 absent, small or homeotic 1 at Arabidopsis thaliana ATP Adenosine-5'-triphosphate BRCT BRCA1 C Terminus Caf-1 chromatin assembly factor 1 Cbx chromobox homolog CDK cyclin dependent kinase ChIP chromatin immuno precipitation CLF CURLY LEAF CpG cytosine-guanine dinucleotide dm Drosophila melanogaster DNA deoxyribonucleic acid Dnmt1 DNA methyltransferase 1 E(z) enhancer of zeste EAF3 Esa1p-associated factor 3 EED embryonic ectodermal development EMF2 EMBRYONIC FLOWER2
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