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Dissecting the Molecular Mechanism and Spatiotemporal Dynamics Controlling Senescence Entry Dissecting the molecular mechanism and spatiotemporal dynamics controlling senescence entry Dissertation for the award of the degree Doctor rerum naturalium (Dr. rer. nat) of the Georg-August-Universität Göttingen Within the Doctoral Program International Max Planck Research School for Genome Science of the Georg-August-University School of Science (GAUSS) Submitted by Konstantinos Sofiadis Goettingen, December 2019 Thesis Advisory Committee Prof. Argyris Papantonis (Supervisor) Institute of Pathology, University Medical Center Göttingen Prof. Ralph Kelhenbach Institute of Molecular Biology, University Medical Center Göttingen Prof. Matthias Dobbelstein Institute of Molecular Oncology, University Medical Center Göttingen Members of Examination Board First Reviewer: Prof Argyris Papantonis (Supervisor) Institute of Pathology, University Medical Center Göttingen Second Reviewer: Prof. Nico Posnien Department of Developmental Biology, Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology, Georg-August-University Göttingen Extended Examination Board Prof. Michael Zeisberg Department of Nephrology und Rheumatology Universitätsmedizin Göttingen Dr. Ufuk Günesdogan Department of Developmental Biology, Göttingen Center for Molecular Biosciences, University of Göttingen PD. Dr. Laura Zelarayán-Behrend Institute of Pharmacology and Toxicology, University Medical Center Göttingen Date of oral examination: February 10th, 2019 Page | 2 Page | 3 Acknowledgements The first words of this manuscripts marks the last moments of a four-year journey that started when I first stepped at the Center of Molecular Medicine of Cologne to start my PhD. A journey that did not seem that long, because it was full of priceless experiences, memories feelings and The first words of this manuscript mark the last moments of a four-year journey that started when I first stepped at the Center of Molecular Medicine of Cologne to start my PhD. A journey that does not seem that long, because it was full of priceless experiences, memories feelings and knowledge. Of course, hard moments, stressful days and sad feelings were not absent, but a moment of happiness would always show up to make up for them. This journey offered me the means to satisfy my scientific interests and opened the door to enter the magical world of science. During this PhD journey a smart person told me that a PhD is not only about the scientific part· it also about changing you as a human being and making you a better person. I hope that I took a step forward in that direction. This previous line belongs to Prof. Argyris Papantonis, who offered me the opportunity that I was looking for many months, while anxiety was gradually accumulating. It is very hard to find the exact words to describe and thank him for these years. It is hard to realize if I respect him more for his bright, (not only) scientific brain or for his amazing personality. A wonderful mentor, a role model, a boss with smart motivational skills other than yelling or misbehaving. A glimpse of enthusiasm and interest for your work from his side and suddenly you find yourself on the bench trying harder and harder. Outside of work, a very amusing company. I have learned so much during these years next to you Fortunately, more people contributed to make my PhD an amazing experience. I was very lucky to meet very nice people and great instructors. I am very grateful for having Dr. Anne Zirkel, a postdoc back in the lab in Cologne, as a direct supervisor of mine. She really set me in the scientific rails and tried hard to teach me, apart from the scientific part, discipline and responsibility. She was always supervising me with patience and sincere guidance. Her continuous encouragement helped me successfully overcome the difficulties during the beginning of my PhD. Two meters away from my office, I could always find Dr. Theodore Georgomanolis, our Lab Manager. At least Lab Manager in the beginning, short after a good friend. I learned so many things from Theo and he was always there to help me when I was struggling. Most importantly a fun person to spend some time during the day in order to relax a bit and discuss any random topic. What should I say for Natasa Josipovic? Anyway, I have learned to be careful with my words around you (kidding!). We started our PhDs almost at the same time and soon developed a beautiful friendship. Always fair, always tough, but paradoxically always sensitive. We were always there to Page | 4 support each other scientifically and mentally. Luckily, a third person shared the load of complaints, fun and party nights. Spyridon Palikyras you are a very good friend and a great host. A friend that appreciates all my silly jokes and vice versa. Of course, I would need several lines to thank all the rest of the members of the lab both in Goettingen and in Cologne. Great scientists, but most importantly very nice people. They were all working hard to establish a professional environment in which each of us could develop individually or as a team. Constant communication and scientific discussion was part of our daily routine, and this taught me so much and really broadened my scientific interests. Finally, the moments we were fed up from work pressure, a call would lead us all to the round table in the kitchen for some coffee and fun discussions. Each one of you played a part in enjoying my PhD years I would like to thank my committee members especially Prof. Ralf Kehlenbach and Prof. Nico Posnien for being my TAC, especially Prof. Posnien who agreed to review my thesis. I am also grateful to Prof. Michael Zeisberg and Dr. Ufuk Guenesdogan for agreeing to be on my examination committee. Outside the scientific community, there were people that really supported me all these years. My best friends “Billares” (Vassilis Nikolaou, Vassilis Tselios) during my bachelor years and up to date, even from far away they are always there when I need them. I know that the plan to do our PhDs at the same place did not work out well, but we managed to find a way to feel close together. Similarly, I want to thank my best friends from my childhood. They are so many and I will probably need unlimited space to write about them. I miss you all guys. Finally, I would like to thank Christina for all the very nice memories and the fun we have had together all these years. I know it was hard (and oftentimes annoying) for you to understand the reasons that kept me so many weekends in the lab, but still you were patient and willing to deal with it. Last part in Greek for my family. Το μεγαλύτερο ευχαριστώ το χρωστάω στους γονείς μου. Στους καλύτερους γονείς του κόσμου οπως δεν θα ντρεπόταν να πει ο πεντάχρονος εαυτός μου. Θυσίασαν τη ζωή τους, το κόπο τους να με/μας στηρίξουν δίνοντας ανιδιοτελώς και ισότιμα ότι είχαν και δεν είχαν για να πραγματοποιήσουμε τα όνειρα μας. Μπαμπα πιθανόν σου στέρησα μερικά χρόνια απο τη ζωή σου εκεινα τα δυσκολα βραδυα (ξερεις εσυ) και ελπιζω η χαρά και η υπερήφανεια που ξέρω ότι θα νιώσεις να σου επιστρέψουν μερικά απο αυτά. Μαμά σε ευχαριστώ που δεν ήσουν η τυπική ελληνίδα μάνα του ζακέτα να πάρεις. Πάντα με απεριόριστη αγάπη αλλά ποτέ με αυταπάτες. Το παράδειγμα εργατικότητας και αφοσίωσης και των δυο σας και είναι οδηγός για μένα. Τέλος ευχαριστώ τον αδερφό για μου και την αδερφή μου για την αγάπη τους και τη στήριξης τους, όσο και αν μας στεναχωρεί όλους που δεν είμαστε κοντά. Page | 5 Table of Contents 1.Summary .........................................................................................................................................9 2. Introduction .................................................................................................................................. 10 2.1 The three-dimensional genome organization in the eukaryotic cell ........................................... 10 2.2 The crosstalk between 3D genome organization and transcription ............................................ 14 2.3 Cellular senescence: A complex cellular mechanism in the defense against tumour as a suitable model of 3D genome organization ................................................................................................. 18 2.3 Cellular senescence is a diverse cellular program with multiple stimuli and signaling pathways ..................................................................................................................................................... 18 2.4 Senescence-associated biomarkers ........................................................................................... 20 2.5 Features of cellular senescence ................................................................................................ 21 2.6 The interplay between 3D genome architecture and senescence/aging ...................................... 24 2.7 High mobility group proteins: abundant nuclear protein in the organization pf the genome ...... 29 2.8 HMGBs in the induction of senescence ................................................................................... 31 2.9 The aim of this study ............................................................................................................... 34 3. Results .......................................................................................................................................... 35 3.1 Chapter I – HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types ..............................................................................................
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