Structural Studies of Transcriptional Silencing

描述（申请人提供）：基因表达的表观遗传控制在真核生物生物学中起着重要作用。表观遗传调控的例子包括发育和分化细胞中Hox基因表达的控制、剂量补偿和衰老。许多癌症与表观遗传调控的改变有关，这涉及到高阶染色质结构的组装。本研究的重点是研究高阶染色质结构建立和维持的分子机制。

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.