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The Transcriptional and Epigenetic Role of Brd4 in the Regulation of the Cellular Stress Response

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The Transcriptional and Epigenetic Role of Brd4 in the Regulation of the Cellular Stress Response THE TRANSCRIPTIONAL AND EPIGENETIC ROLE OF BRD4 IN THE REGULATION OF THE CELLULAR STRESS RESPONSE INAUGURAL-DISSERTATION to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Michelle Hussong from Zweibrücken 2015 Die vorliegende Arbeit wurde im Zeitraum von Juli 2012 bis September 2015 am Max- Planck-Institut für Molekulare Genetik in Berlin sowie an der Universität zu Köln unter der Leitung von Frau Prof. Dr. Dr. Michal-Ruth Schweiger angefertigt. 1. Gutachter: Prof. Dr. Dr. Michal-Ruth Schweiger 2. Gutachter: Prof. Dr. Rupert Mutzel Disputation am 07.12.2015 ACKNOWLEDGMENT ACKNOWLEDGMENT This dissertation would not have been possible without the guidance and the help of many people who in one way or another contributed to the preparation and completion of this study. Firstly, I would like to express my sincere gratitude to my advisor Prof. Dr. Dr. Michal-Ruth Schweiger, for her continuous support throughout my PhD study, for her patience, motivation, and immense knowledge. I am eminently thankful for the multiple possibilities she gave me to work on this interesting and challenging field of research. I also want to thank Professor Dr. Rupert Mutzel for taking the time of being my second supervisor. My sincere thanks also goes to Prof. Dr. Hans Lehrach for having given me the opportunity to do my PhD thesis in the extraordinary and inspiring environment at the Max-Planck- Institute for Molecular Genetics in Berlin. Especially, the multitude of technologies and knowledge in his department made my work successful. This thesis would not have been possible without the help of many people. Many thanks to Prof. Dr. Monica Hirsch-Kauffmann for her never-ending support, inspiring suggestions and interesting discussions. A special thanks to Dr. Martin Kerick, who performed all the sequencing data analysis. This work would not have been possible without his invaluable knowledge and support. In this regard I also want to say thanks to the sequencing core facility around Dr. Bernd Timmermann. I'd especially like to thank Dr. Christian Kähler and Dr. Sylvia Krobitsch for their huge knowledge in the field of heat stress research, for performing the immunofluorescence experiments and for their feedback and suggestions on the manuscript. Furthermore, I'd like to thank Dr. Jörg Isenssee for conducting the quantitative high-content screening microscopy. I want to thank all former members of the Schweiger lab, especially Dr. Stefan Börno and Dr. Andrea Wunderlich for their support in experiments, for interesting and fruitful discussions and for their contribution and comments on the manuscript. Many thanks also to Nada Kumer who was always a great help in the lab. I’m very grateful to my present colleagues for the friendly atmosphere in the lab. Many thanks to Christina Grimm, Sabrina Grasse, Susann Siebert and Anne Steinbach who all contributed to making our lab a happy place. I ACKNOWLEDGMENT My special thanks go to Sabrina Grasse for all the fun we have had in the last three years. I am especially grateful to get such a good friend even outside of work. I also gratefully acknowledge the “Studienstiftung des Deutschen Volkes” for their financial support throughout my PhD study. Last but not the least, my deepest debt is to my family, my parents and my sister for their everlasting support and encouragement throughout writing this thesis and my whole life in general. II ZUSAMMENFASSUNG ZUSAMMENFASSUNG Die zelluläre Stressantwort umfasst die Anpassung eines Organismus auf umweltbedingte und endogene Stressfaktoren, welche durch eine Vielzahl von molekularen Prozessen gesteuert wird. Eine Deregulierung dieser Antwort ist ein Indikator und möglicher Auslöser vieler Krankheiten, insbesondere Tumorerkrankungen, und bietet daher einen interessanten Angriffspunkt für Therapien. Ein sehr wichtiges und für die Tumorforschung auch aus therapeutischer Sicht äußerst vielversprechendes Protein ist das Bromodomänen enthaltende Protein 4, kurz BRD4. BRD4 spielt in sehr vielen Bereichen der Zelle eine wichtige Rolle, unter anderem als epigenetischer Sensor sowie transkriptioneller Regulator und ist damit ein wichtiges Bindeglied zwischen dem transkriptionellen Prozess und epigenetischen Mustern. Ziel dieser Arbeit war es, die Rolle von BRD4 bei der epigenetischen, als auch der transkriptionellen Regulation im Verlauf von zellulären Stressantworten zu untersuchen. Durch Genexpressionsanalysen in BRD4-defizienten Zellen, sowie Chromatin-Protein- Interaktionsstudien konnte ich 52 BRD4-regulierte Zielgene identifizieren, welche vor allem für Proteine der oxidativen Stressantwort sowie der Hitzestressantwort kodieren. Weiterführende Analysen identifizierten BRD4 als einen wichtigen Modulator eines der wichtigsten, mit oxidativem Stress assoziierten Signalwege, dem KEAP1/NRF2 Signalweg. Durch eine transkriptionelle Regulierung von KEAP1 kontrolliert BRD4 die Aktivität des Transkriptionsfaktors NRF2, welche wiederum die Expression zytoprotektiver Gene induziert. Eine Hemmung der BRD4 Aktivität führt unter Stress-Bedingungen zu einer Verringerung an reaktiven Sauerstoffspezies (ROS) in der Zelle und zu einem Schutz der Zellen vor oxidativem Stress-vermittelten Zelltod. Zudem konnte ich anhand einer Vielzahl von molekularbiologischen Experimenten zeigen, dass BRD4 direkt die Expression von HMOX1, einem ROS-regulierendes Protein, über eine Bindung an den Transkriptionsfaktor SP1, reguliert. Dieses transkriptionelle Regulationsnetzwerk scheint bei Prostatakrebs gestört zu sein, was möglicherweise eine zentrale Rolle beim malignen Prozess der Tumorentstehung spielt. Zusätzlich zu seiner Funktion bei der transkriptionellen Regulation gibt es bereits einige Hinweise, die eine Rolle von BRD4 bei dem zellulären Spleißprozess wahrscheinlich machen. III ZUSAMMENFASSUNG Im Rahmen meiner Arbeit konnte ich zeigen, dass BRD4 eine wichtige Rolle bei dem Spleißvorgang unter Hitzestress spielt. So fördert es das, unter Hitzestress beeinträchtigte, Herausschneiden von Introns. Weitere molekularbiologische Analysen zeigten, dass unter diesen Stressbedingungen BRD4 in sub-nukleären Strukturen, den sogenannten „nuclear stress bodies“, rekrutiert wird. Dort aktiviert BRD4, zusammen mit dem Hitzeschock Faktor HSF1, die Transkription von nicht-kodierenden Sat III RNAs. Diese werden als wichtige Modulatoren der Stress- induzierten Spleißreaktion diskutiert. Zusammenfassend konnte ich zeigen, dass BRD4 sowohl in die Transkiption, als auch in den Spleissprozess unter zellulärem Stress involviert ist. Dies stellt eine weitere Grundlage dar, Pathomechanismen der Tumorentstehung besser zu verstehen, aber auch, um neue Therapieansätze zu entwickeln. IV SUMMARY SUMMARY The cellular stress response describes the adaptation of an organism to environmental stressors by a variety of molecular changes. Deregulation of this response is an indicator and possible promoter of many diseases, in particular cancers, and therefore offers an interesting target for tumor therapies. A for the tumor therapy very promising target is the bromodomains containing protein 4 (BRD4). BRD4 plays a significant role in many cellular processes: It is an epigenetic reader and transcriptional regulator and therefore links the transcription process to epigenetic patterns. The aim of this study was to further understand the role of BRD4 in the epigenetic and transcriptional regulation of cellular stress responses. Through genome-wide gene expression profiling in BRD4-deficient cells, and chromatin-protein interaction studies, I was able to identify 52 BRD4-regulated target genes, mainly encoded for proteins of the oxidative stress - and heat stress response. Further analyses highlighted BRD4 as regulator of the oxidative stress-induced KEAP1/NRF2 signalling pathway. By regulating the transcription of KEAP1, BRD4 modulates the activity of the transcription factor NRF2 and, in turn, the expression of cyto-protective genes under stress. An inhibition of BRD4 resulted in decreased reactive oxygen species (ROS) production and protected cells from oxidative stress mediated cell death. In addition, BRD4 also interacts with the transcription factor SP1 and directly regulates the expression of HMOX1, a ROS reducing protein. Remarkably, this regulatory network is disrupted in prostate cancer and thus might play a central role in tumorigenesis. Furthermore, using RNA-sequencing analyses of BRD4-deficient and heat treated cells I showed that a reduction of BRD4 expression increased the heat shock-mediated splicing inhibition, in particular intron retentions. Subsequent experiments revealed that under heat stress BRD4 binds to the heat shock factor 1 (HSF1), which leads to the recruitment of BRD4 to sub-nuclear structures, the so- called "nuclear stress bodies". The translocation of BRD4 is associated with the transcriptional activation of non-coding Sat III RNA expression. Sat III RNAs, in turn, are discussed as important modulators of the stress-induced splicing process. Taken together, my results link BRD4 not only to the transcription machinery, but also to the splicing process under oxidative or heat stress, respectively. This gives additional insights into the mode of action of BRD4 inhibitors and could lay the foundation for the development of new therapeutic strategies. V VI TABLE OF CONTENT TABLE OF CONTENT ACKNOWLEDGMENT .....................................................................................................................
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