Structural Studies of Transcriptional Silencing

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DESCRIPTION (provided by applicant): Epigenetic control of gene expression plays important roles in eukaryotic biology. Examples of epigenetic regulation include control of Hox gene expression during development and in differentiated cells, dosage compensation and aging. Many cancers are associated with altered epigenetic regulation, which involves the assembly of higher order chromatin structures. This proposal focuses on studying the molecular mechanisms by which higher order chromatin structures are established and maintained. We use X-ray crystallography as our main tool to study mechanisms by which epigenetic regulators are recruited to the silent genomic loci, structures and functions of histone modification enzymes, and the recognition of histone codes. We will study in parallel the genetically well-characterized mating-type silencing in S. cerevisiae and chromatin-associated proteins in humans. The study should provide mechanistic understanding of heterochromatin assembly in yeast, as well as providing important insights into mechanisms of epigenetic regulation of gene expression in humans. The atomic-resolution structures may also be used to aid the development of therapeutic agents against cancer.