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Stochastic Modelling of Epigenetic Regulation: Analysis of Its Heterogeneity and Its Implications in Cell Plasticity

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Stochastic Modelling of Epigenetic Regulation: Analysis of Its Heterogeneity and Its Implications in Cell Plasticity ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Stochastic modelling of epigenetic regulation: analysis of its heterogeneity and its implications in cell plasticity Tesi Doctoral Autora: N´uriaFolguera Blasco Director: Tom´asAlarc´onCor Codirector: Javier Men´endezMen´endez Universitat Aut`onomade Barcelona (UAB) Centre de Recerca Matem`atica(CRM) Programa de Doctorat en Matem`atiques Setembre de 2018 A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Mathematics at the Universitat Aut`onomade Barcelona September 2018 We are more than the sum of our genes. Klar, 1998 ii Abstract Epigenetic regulation (ER) is key for understanding cell fate decisions and transi- tions. The inherent heterogeneity existing in ER systems exhibiting the differentiated cell epi-phenotype allows to identify ER systems which can give rise to either a plastic behaviour, where cell reprogramming is possible, or to a resilient one, where repro- gramming is not feasible. The appearance of the plastic scenario has been linked with ageing. By extending the ER model, ageing associated effects can be taken into account. The extended ER model allows us to define a healthy plastic scenario. When further dysregulations of the ER system are considered, a pathological form of reprogramming is identified so that the ER system gets locked in a non-differentiated state. When coupling ER to a gene regulatory network (GRN) model, the ability of the ER systems to switch state allows us to identify differentiation-primed and pluripotency-locked systems, as well as to design strategies able to unlock those cells that remain in a stem cell like state. These strategies may be of key importance in order to avoid cancer progression. Acknowledgements Firstly, I would like to acknowledge my supervisor, Tom´asAlarc´on.I would need lots of pages to thank him for many things, but I will summarise how he has made me feel from the very beginning to the end of these 4 years. I still remember the phone call he gave me when I was studying my MSc in Bath. At that moment, he told me that he had a very nice project in mind and that he thought that I could be a good candidate for it. He could not be more right! He was absolutely right when stating that the project was nice. In fact, it was, and still is, awesome! I would be always grateful to you, Tom´as,for having given me this nice project and having relied on me for carrying out this research idea. As you know, Tom´as,I have loved this project a lot, I have really got passionated about it and I think this is also because of you. You have worked hard with me in order to make the most of it and I think we have done it quite well. That day, when you called me, I felt that you were valuing me a lot. And I have had this feeling during all the PhD. You have given me valuable support whenever I have needed, not just scientifically. You have provide me advice in research and future career and you have been implied in this project as much as I have been (even reading this thesis during August to make suggestions and corrections to improve it, for which I am extremely grateful). Furthermore, you have created a really nice working atmosphere where I have never felt like being somebody at a lower level. You have treated me as if I were a researcher to whom you could discuss anything. In some cases, I was not clearly at the same level as you were, but in these cases, you had the patience to explain me whatever was needed. With you, I have laughed a lot because you have this nice way of approaching research, and life in general. All this has made me feel really comfortable working with you. I could write lots of positive things about you, but I know that I need to stop at some point. I would stop in here by saying that when I came back from the UK for the PhD you offered me, I was hesitating a lot if I had taken the right decision or not. Right now, I have no single doubt that that decision is probably one of the best I have ever taken. So, from the deep of my heart, thank you so much Tom´as. As you know, and as I have told you so many times, if I could, I would stay at CRM working with you. It has been an incredible pleasure. As I have just mentioned, if I could, I would stay at CRM. And this is partly thanks to Tom´as,but not only because of him. CRM has been to me like a second home and I have felt really valued and appreciated. It is really nice going to work feeling like this. I start by thanking Joaquim Bruna, the former director, for awarding me one of the scholarships from `La Caixa Foundation'. Consequently, I would like i to extend my gratitude to `La Caixa Foundation' for its funding during these PhD years. Thank you for funding research in Collaborative Mathematics, something I really believe in. Regarding funding, I would also like to thank Fundaci´oFerran Sunyer i Balaguer for giving me a travel scholarship which allowed me to work at the Mathematical Institute in Oxford. During my PhD period, I have met at CRM incredible people who started being my office mates and who now they have become my friends. I would like to say some words about them since I have to acknowledge them for many reasons. To Gemma, I am really grateful for always being there ready to listen, to talk or to let me use her computer to run my simulations. To Roberto, for being a really nice group mate willing to help and for staying late with me in the office, so I was not alone. To V´ıctor,for always making me laugh, something really needed, specially in those days where research does not work the way you want. To Daria, for her extremely nice ability for drawing awesome plots (like the `supercell') and for her passion for helping, both in research and in life. To Claudia, for her kindness, her `extraempathy' sense and for her ability to see when you need somebody to cheer you up. To Marc, for sharing the musical moments and the craziness. To Alberto, Carmelo, Gen´ısand Bernat for making lunch time a really funny part of the day and the perfect disconnection moment. Special mention goes to Marina and Carles, who have been an extension of my family. You have always been there. Marina and Carles, Carles and Marina, I have shared really special moments with you. You have listened to me, given advice and you have treated me as if I was part of your family. I have no words to describe how you have made me feel. I find it hard to find people to whom I can really trust and connect, but with you, from the very beginning, it has been very different. I don't know exactly why, but, I guess the answer is on you. I am sure that one of the best things the PhD has given me is meeting you, and I will not let go. No matter how far we are, because I know that a part of you goes with me. From you, I have learned both to be a better person and to be more critical about everything surrounding us. I admire your fairness and kindness, the way you approach life in general. You fight for your ideals regardless of what others think or where the world is leading to. You are not afraid of saying your thoughts. I strongly believe that the world needs more people like you, as this is the only way progress will be made. So many thanks for all what you have showed me. I have become a better human, which is priceless, and all because of you. Thanks for letting me enter in your lives. ii At CRM, I have also met other research staff who have made the PhD period better. I thanks Juan for listening and givimg advice. I thanks Josep for trying to help with all his contacts and trying to look for collaborations. To Isa, my gratitude for always been thinking about me and trying to involve me in any project she had in mind. I really appreciate it! And, of course, to Alvaro,´ for his incredible sense of humour, and for his lovely e-mails, which I am already missing. Alvaro,´ you have been really kind with me. Many thanks! In general, I would have nice words for `almost' all the people I have met at CRM. Hence, I would also like to thank people from administration. I thank N´uria,Ana, Alba, Consol, Pau, Mari Paz, Angels` and Arantxa for treating me so well. I also thanks Jordi for his patience with all my computer problems.
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