We intend to achieve a step change in our understanding of the mechanistic basis of epigenetic regulation. We will capitalize on a plant epigenetic silencing system, vernalization, which has many features that allow the complete dissection of different facets of epigenetic regulation. In addition, the silencing is quantitatively modulated by the environment enabling dissection of how external cues mediate epigenetic silencing. We will combine genetics, molecular biology and biochemical approaches with computational modelling to allow us to translate the extensive nuts and bolts information into an understanding of how the engine works. A particular strength of modelling will be its predictive nature and ability to distinguish between key components and those with subsidiary or redundant roles. The system we will use is vernalization, the cold-induced Polycomb-silencing of the target locus, FLC. We will dissect the many phases of vernalization: the triggering of FLC repression by prolonged cold; the nucleation and epigenetic stability of chromatin changes at FLC; and the spreading of the silencing yet spatial restriction to FLC. Our goal will be a full understanding of the complexity involved in the epigenetic silencing of this locus, described in a quantitative model that reveals how the silencing is induced by temperature and how individual components of the silencing network are integrated into a robust whole. This ambitious goal, which will uncover fundamental concepts important to gene regulation in many organisms, will be achieved through a tight integration of molecular analysis and computational modelling, enabling efficient cycling between experimentation, prediction and validation.
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