Sepideh Khorasanizadeh, PhD
Structural biology of epigenetic signaling (HDAC and Methylation inhibitors)
The regulatory signals provided by chromatin modification allow the epigenetic marking of genomes. These epigenetic events are important factors in cancer development. The Khorasanizadeh's laboratory has been providing three-dimensional structures of complexes that visualize histone tail modification and recognition. Using a combination of NMR and crystallography, they have described how enzymes (SET domain) can methylate histone tails and how conserved modules (chromodomain) then recognize these specific post-translational marks. Additional insights from calorimetry and mutagenesis are making it possible to uncover the thermodynamic basis for selective recognition of methyllysines on chromatin. They are also implementing a novel synthetic combinatorial peptide selection assay to discover the true targets for poorly characterized chromodomains. All of these studies are supported by in-vivo immuno-fluorescence studies in Drosophila S2 cells and polytene chromosomes that examine the co-localization of marking and recognition elements. The next phase of their studies is designed to focus on entire nucleosomal complexes in which specific histone modification and recognition factors are trapped for direct visualization.