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Systematic Analysis of Lysine Acetyltransferases Dissertation zur Erlangung des akademischen Grades Dr. rer. nat. vorgelegt der Fakultät für Biologie der Ludwig-Maximilians-Universität München Christian Feller München 2014 1. Gutachter: Prof. Dr. Peter B. Becker 2. Gutachter: Prof. Dr. Dirk Eick Dissertation eingereicht am: 16.09.2014 Mündliche Prüfung am: 28.10.2014 Eidesstattliche Erklärung Ich versichere hiermit an Eides statt, dass die vorgelegte Dissertation von mir selbstständig und ohne unerlaubte Hilfe angefertigt ist. München, den 15. September 2014 .................................... (Christian Feller) Erklärung Hiermit erkläre ich, dass die vorgelegte Arbeit an der LMU von Herrn Prof. Dr. Peter Becker betreut wurde. Hiermit erkläre ich, dass die Dissertation nicht ganz oder in Teilen einer anderen Prüfungskommission vorgelegt worden ist. Weiterhin habe ich weder an einem anderen Ort eine Promotion angestrebt noch angemeldet, noch versucht eine Doktorprüfung abzulegen. Die eigenen Leistungen für die in dieser kumulativen Dissertation enthaltenen Manuskripte sind in den Kapiteln 3.1.1, 3.2.1, 3.3.1 und 3.4.1 aufgelistet. München, den 15. September 2014 .................................... (Christian Feller) For my parents Table of contents 1 SUMMARY ................................................................................................................................. 11 2 INTRODUCTION ........................................................................................................................ 15 2.1 The nucleosome is the basic repeat unit of chromatin ........................................................ 16 2.2 Higher-order chromatin structures ...................................................................................... 18 2.3 Post-translational histone modifications ............................................................................. 20 2.3.1 Lysine acetylation .............................................................................................................. 21 2.3.2 Lysine methylation ............................................................................................................. 30 2.4 Dosage compensation in the fruit fly Drosophila melanogaster ......................................... 33 3 RESULTS AND DISCUSSION ..................................................................................................... 36 3.1 The activation potential of MOF is constrained for dosage compensation ......................... 37 3.1.1 Summary, significance and own contribution .................................................................... 38 3.1.2 Published manuscript ......................................................................................................... 40 3.1.3 Supplementary data and figures ......................................................................................... 53 3.2 Dosage compensation and the global re-balancing of aneuploid genomes ......................... 72 3.2.1 Summary and own contribution ......................................................................................... 73 3.2.2 Published review article ..................................................................................................... 74 3.3 The MOF-containing NSL complex associates globally with housekeeping genes, but activates only a defined subset .......................................................................... 83 3.3.1 Summary, significance and own contribution .................................................................... 84 3.3.2 Published manuscript ......................................................................................................... 86 3.3.3 Supplementary data and figures ....................................................................................... 101 3.4 Global and specific responses of the histone acetylome to systematic perturbation ....................................................................................................................... 114 3.4.1 Summary, significance and own contribution .................................................................. 115 3.4.2 Submitted manuscript ....................................................................................................... 117 3.4.3 Supplementary data, tables and figures ............................................................................ 151 3.4.4 Discussion on substrate specificity of lysine acetyltransferases using the examples of HAT1 and HBO1 .......................................................................... 203 4 GENERAL CONCLUSIONS AND OUTLOOK ......................................................................... 208 5 REFERENCES ............................................................................................................................. 213 6 ACKNOWLEDGEMENTS .......................................................................................................... 236 7 LIST OF ABBREVIATIONS ....................................................................................................... 238 8 CURRICULUM VITAE ............................................................................................................... 241 SUMMARY 11 1 SUMMARY Eukaryotic genomes are packed in chromatin that comprises an ever repeating succession of nucleosomes with DNA wrapped around octamers of histone proteins. Dynamic regulation of chromatin structure enables controllable access to the underlying DNA and hence is crucial to all nuclear processes, including DNA transcription, replication and repair. Many interconnected mechanisms are in place to regulate chromatin structure. These include chemical modifications of histone proteins, such as lysine acetylation and methylation, which directly alter the properties of nucleosomes to form repressive structures or install signaling marks for dedicated effector proteins. The original research described in this cumulative thesis is contained in two published articles and one submitted manuscript centering on histone lysine acetylation in Drosophila melanogaster. In the first two articles, we characterise the functions of two multi-protein complexes containing the lysine acetyltransferase MOF (males absent on the first). If incorporated in the male-specific lethal dosage compensation complex (MSL-DCC) MOF acetylates lysine 16 on histone H4 (H4.K16ac) on gene bodies on the male X chromosome, which is critical for the two-fold transcriptional stimulation of its target genes. The underlying process, dosage compensation, serves to adjust gene expression levels between the single male and the two female X chromosomes. Combining genome-wide mapping and transcriptome studies with the analysis of defined reporter loci in transgenic flies and cell lines, we provided evidence that MOF-mediated H4.K16ac has an inherent strong transcriptional activation potential, which is, however, constrained to the physiological two-fold range in the context of fly dosage compensation. In contrast, MOF as a component of the non-specific lethal (NSL) complex binds promoters of active housekeeping genes located on all chromosomes in male and female flies. However, transcriptional activation through the NSL complex is found only at a subset of these binding sites. These NSL-regulated genes are enriched for a specific core promoter sequence and depleted for the insulator proteins CP190 and BEAF as well as the heterochromatin protein HP1c. In summary, these studies describe the context-specific localization and transcriptional activation modes of the acetyltransferase MOF through its incorporation into two distinct multi-protein complexes. Histones have acquired impressive patterns of acetylation sites, where the individual abundance and the context of co-occurrence with other marks potentially confers very different functions. However, the current methodologies are too limited to systematically evaluate changes in rare and combinatorial modification motifs. Moreover, how different enzymes contribute to complex motifs is only poorly understood. In the third study, we generated a catalogue of histone acetylation and methylation motifs that describe the changes in response to ablation of every known or suspected lysine acetyltransferase and deacetylase. To achieve this goal, we first optimised liquid chromatography mass spectrometry workflows that enabled highly accurate and precise quantification of combinatorial histone SUMMARY 12 modification motifs. The comprehensiveness of the dataset not only allowed us to recognise class- specific properties to these enzyme families but also to describe the histone modification system as an interconnected, flexible network that compensates the loss of an individual component. We describe the specific responses of the histone acetylome upon ablation of each acetyltransferase. To our surprise we also observed that depletion of almost every acetyltransferase triggered a systemic response that effectively maintained global histone acetylation levels. Finally, we documented that dosage compensation is not restricted to the change of the single H4.K16ac mark, but accompanied by a specific re-distribution of acetylation and methylation motifs. In summary, this study provides further evidence that chromatin pathways are highly interconnected and highlights the necessity to study the function of each individual component in the context of the system. SUMMARY 13 ZUSAMMENFASSUNG Eukaryotische Genome sind in einer
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