Leonie Ringrose, Humboldt-Universität zu Berlin

Epigenetic gene regulation is highly stable: epigenetic memory of gene expression states can persist over many cell generations and potentially for longer. However, epigenetic regulation is also flexible: genes that are subject to epigenetic regulation can respond dynamically to environmental and developmental signals. How can epigenetic regulation be both stable and flexible? I propose that the key lies in the highly dynamic nature of epigenetic systems. Over the last two decades it has become clear that the nucleus is an extraordinarily busy and noisy place: many proteins, including epigenetic regulators, are in constant motion, exchanging rapidly between chromatin bound and free states. Quantitative aspects of this motion are highly regulated. I propose that that to fully understand this regulation, epigenetics needs mathematics. We need ‘‘moving models’’ built of mathematical descriptions, which we can feed with measured values of quantities and mobilities of the components. A good model makes testable predictions that tell us whether our hypothesis makes sense. If it does not, we change the model. There has never been a better time to combine theoretical approaches with quantitative experiments. On the theoretical side, the last decade has seen a quiet revolution in the application of models built by physicists to the deep questions of epigenetics. On the experimental side, the advent of technologies that allow real time analysis at the single cell and single molecule level, together with those that enable targeted genome editing, allow precise perturbation and quantitative measurements at an unprecedented level. It is time for epigenetics to meet mathematics. I will give examples from work in the field and in my own lab, of how the fusion of experiment and theory has brought fresh insights into epigenetic regulation that go beyond intuition.

----------- Leonie Ringrose, Humboldt University, Berlin. I am a British molecular biologist on a journey towards theoretical biology. I have been a professor at the IRI for Lifesciences at Humboldt University, Berlin since May 2015 (www.ringroselab.com). From 2006 to 2014 I was a junior group leader at the IMBA (Institute of Molecular Biotechnology) in Vienna. My interest in mathematical modelling and quantitative biology began during my PhD at the EMBL, Heidelberg (1992- 1997), where I used modelling to investigate quantitative aspects of DNA recombination. Since 2018 I have been coordinator of the EU- Marie-Curie Innovative Training Network “PEP-NET: Predictive Epigenetics”. The network will train 15 PhD students Europe-wide, to combine experimental and theoretical approaches to fundamental and applied questions in epigenetics http://itn-pep.net My group works on epigenetic regulation by the Polycomb and Trithorax group proteins in Drosophila and mouse development. These proteins are highly conserved and essential to life, but many aspects of their function are enigmatic. I believe that theoretical approaches, in combination with quantitative experiments, offer great potential for unlocking some of the mysteries of epigenetic regulation. We use a combination of quantitative live imaging, mathematical modeling, computational approaches and molecular and developmental biology to understand the interaction of the Polycomb and Trithorax proteins with their chromatin targets. Our goal is to understand how a system whose components are in constant flux can ensure both stability and flexibility of gene expression states. Contact : F. Palladino