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Dissertation / Doctoral Thesis DISSERTATION / DOCTORAL THESIS Titel der Dissertation /Title of the Doctoral Thesis „Enhancer-responsiveness and -specificity of Core Promoters in Gene Transcription“ verfasst von / submitted by Muhammad Mamduh Ahmad Zabidi angestrebter akademischer Grad / in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) Wien, 2017 / Vienna 2017 Studienkennzahl lt. Studienblatt / A 794 685 490 degree programme code as it appears on the student record sheet: Dissertationsgebiet lt. Studienblatt / Molekulare Biologie field of study as it appears on the student record sheet: Betreut von / Supervisor: Dipl.-Biochem. Dr. AleXander Stark Acknowledgements Acknowledgements First I thank my whole family especially Mum for raising me in this World and teaching me all the good ethics. I thank Alex who made a risky hire on an unproven computational person, for close supervision and all aspects of this thesis. I thank Cosmas for leading the wetlab team to produce the data and for picking up my slack. For Michi and Martina, I thank them for their work in the wetlab, and for their motherly nature that they carry to the lab. I also thank Kathi and Olga for their contributions in the wetlab. I thank Tomáš, Daniel Gerlach and Omar for lots of help when I first started at the computer. Also thanks for Tomáš again for many extra help. Thanks to the rest of the Stark group: Dasha, Lukasz, Fanny, Daniel Spies, Anaïs, Felix, Evgeny, Gerald, Sebastian, Rui, Christoph Neumayr, Christoph Stelzer, Vanja, Ashley, Leo, Antonio, Lukas, Evgeniia, Filip, Mona, Mayela and Ivan. I thank Petar, Lux and Hannes for the high-performance computing cluster. Thanks also to the Vienna Biocenter Core Facilities, especially the next generation sequencing, and the members of the DoktoratsKolleg RNA Biology. Special thanks for Karlo for providing me with a quiet space in the library where I can really delve into the code and engineer the solutions for the biological problems in this thesis. I thank the members of my thesis committee, Julius, Luisa and Florian. I also thank Inês and Chris for an excellent PhD program in the best city in the World. Thanks also to other people from the campus: Dani, Ian, Gordana, David, Kota, June, Olie, Zahra, and many more that I probably have forgotten here. I thank my German teachers from Internationales Kulturinstitut Wien, especially Magdalena who taught me for the first 2 years, as well as Anna, Birgit, and Andreas. The 3 Acknowledgements German knowledge that I have accumulated certainly helps in Vienna. I also thank the small Malaysian community here in Vienna. I especially thank Venu and Harini. Nobody has ever been so kind as to take me in while I recuperate after my ACL surgery. I don’t know how to repay you. And for many more people who I forgot to mention here. Core promoters are made up of core promoter elements that recruit trans factors. You are made up of some traits, with which you would attract people and events, whether you want it or not, knowingly or not. Some life patterns will happen to you and teach you, again and again and again. Until you learn. Core promoters are directional. Life is directional. You waste it, you ain’t getting it back. You can only move forward. So stay healthy. And don’t wander. Core promoters are short. Life is short. When the organism is dead, core promoters don’t matter no more. When you’re dead, nothing matters anymore. I hope other human beings and humanity in general benefit from this thesis. Sincerely yours. 4 Table of Contents Table of Contents Table of Contents ............................................................................................................. 5 Summary .......................................................................................................................... 7 Zusammenfassung ............................................................................................................ 9 Introduction ................................................................................................................... 11 The Genome and Transcription Regulation .................................................................................. 11 Core Promoters as Genetic Elements ........................................................................................... 13 Gene Regulation via Core Promoters: Variegated Forms of Core Promoter Complexes ................ 16 Gene Regulation via Core Promoters: Early Steps of Transcription ............................................... 18 Gene Regulation via Core Promoters: RNA Polymerase II Pausing ............................................... 21 Enhancer-specificity of Core Promoters ....................................................................................... 22 Enhancer-responsiveness of Core Promoters ................................................................................ 25 Aims of the Thesis .......................................................................................................... 29 Results and Discussion ................................................................................................... 31 Paper #1: Enhancer–core-promoter Specificity Separates Developmental and Housekeeping Gene Regulation ................................................................................................................................... 31 Paper #2: Regulatory Enhancer–Core-Promoter Communication via Transcription Factors and Cofactors ..................................................................................................................................... 49 Paper #3: Genome-wide Assessment of Sequence-intrinsic Enhancer Responsiveness at Single- base-pair Resolution .................................................................................................................... 65 Conclusions and Perspectives ........................................................................................ 91 Enhancer-specificity and Biochemical Compatibility ................................................................... 91 Enhancer-specificity in Other Transcription Programs .................................................................. 93 Decoding Enhancer-responsiveness ............................................................................................. 93 Deciphering the Initiation Code ................................................................................................... 94 Enhancer-responsiveness and Transcription Regulation ............................................................... 95 Beyond Enhancer-responsiveness and –specificity ....................................................................... 96 References ..................................................................................................................... 99 5 6 Summary Summary Animal development is attributed to differential gene expression that is tightly regulated. Genes are transcribed from core promoters, sequences of around 100 base pairs (bp) surrounding the transcription start sites (TSSs) at which the RNA Polymerase II (Pol II) complex assembles. The cell-type specific transcriptional activities of core promoters are dependent on a second type of genomic regulatory element termed enhancers. During my PhD, I am interested in the specificity and responsiveness of core promoters towards enhancers. An open question in the study of transcription is whether core promoters display intrinsic preferences towards enhancers. To address this hypothesis, we tested genome- wide enhancer candidates for their ability to activate core promoters that represent the housekeeping or developmental transcription programs, respectively. In Drosophila melanogaster cell lines, the two core promoter types exhibit differential preferences towards thousands of enhancers. Housekeeping core promoters are activated by enhancers that are active across cell types, while developmental core promoters are activated by enhancers that are highly cell-type specific. These two enhancer classes also differ in their genomic location, the protein factors that they bind, and the function of the neighbouring genes. Different core promoters do not always support transcription at the same level, differences that have been mainly attributed to the wide range of enhancer strengths. Little is known about the intrinsic responsiveness of core promoters towards enhancers. We used single defined enhancers to test the enhancer-responsiveness of genome-wide core promoter candidates from Drosophila melanogaster. Core promoters vary widely in their enhancer-responsiveness, with differences up to three orders of magnitude. The differences correlate with sequence signatures and are associated with genes of different function. In summary, the results obtained during my PhD thesis project show that the preference of core promoters towards enhancers represent another mechanism of 7 Summary enhancer–core-promoter communication, and the thousands of core promoters in the genome vary substantially in their enhancer-responsiveness. These findings demonstrate that core promoters are actively involved in the precisely regulated gene expression that drives animal development. 8 Zusammenfassung Zusammenfassung Differenzielle Genexpression ist entscheidend für die Entwicklung mehrzelliger Lebewesen wie Menschen und Tiere und muss daher streng kontrolliert werden. Gene werden beginnend von einer etwa 100 Basenpaare langen DNA Sequenz transkribiert. Diese Sequenz wird als
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