Gene regulation with a twist: Exploring the dynamic chromatin landscape
Abstract: The dynamic organization of the eukaryotic genome into chromatin is integral to genome regulation. Chromatin structure and dynamics, modulated by histone post-translational modifications (PTMs) as well as architectural proteins, dictate DNA access for transcription factors and the gene expression machinery. While of key importance, the detailed mechanisms of DNA access regulation by chromatin dynamics are still poorly understood.
We are developing chemical biology and biophysical approaches to investigate the dynamic function of post-translationally modified chromatin in gene activation and repression. Applying these methods, we have shown how multivalent effectors, such as polycomb repressive complex 2 (PRC2) interact with and regulate chromatin function in vitro and in stem cells. Recently, we established a new single-molecule FRET method to directly measure structural dynamics in chemically defined chromatin fibers. We detected multiscale motions within and between nucleosomes, providing a first detailed description of chromatin conformational dynamics. This allowed us to dissect how pioneer transcription factors can access compact chromatin, open and remodel chromatin structure thereby enabling gene activation.
In summary, our studies reveal a new dynamic picture of chromatin and allow a molecular understanding of its regulation by combinations histone PTMs, multivalent effectors and transcription factors.
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery