"This project will develop a highly sophisticated coarse-grained model of chromatin fibers from precise all-atom simulations of dinucleosomes and DNA segments. The purpose of the proposed project is to enhance our understanding of the mechanism by which different patterns of epigenetic modifications (of DNA and histone proteins) interact with each other to control the structure of the chromatin fiber and regulate gene expression. Our modelling strategy will be based on landmark experimental studies and will provide a novel method by which to understand the combined effects of histone epigenetic modifications and DNA methylation in higher-order chromatin structure. With our coarse-grained model we will perform a systematic study to elucidate if specific combinations and distributions of epigenetic modifications work cooperatively to yield a particular organization of the chromatin fiber, or in contrast, if the effect of multiple epigenetic marks is averaged out leading to fiber stability and favouring a heteromorphic chromatin structure with optimal compaction. Deciphering how epigenetic marks interact with each other to control chromatin organization is one most fundamental open biological questions today. This information is important not only from a scientific perspective, but also crucial to understand aberrant gene expression and it relationship to life-threatening diseases such as cancer. Given the inherent complexity of this problem, an approach that bridges experiments and theory, such as the one proposed here, is essential to close gaps in understanding."
Fields of science
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