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学中发挥着重要作用。表观遗传调控的例子包括控制发育期间和分化细胞中HOX基因的表达，剂量补偿和衰老。许多癌症与表观遗传调控的改变有关，表观遗传调控涉及高阶染色质结构的组装。这项建议侧重于研究高阶染色质结构建立和维持的分子机制。 我们使用X射线结晶学作为我们的主要工具来研究表观遗传调节因子被招募到沉默的基因组座位的机制，组蛋白修饰酶的结构和功能，以及组蛋白密码的识别。我们将同时研究酿酒酵母和人类染色质相关蛋白中具有良好遗传特征的交配型沉默。这项研究应该提供对酵母中异染色质组装的机制的理解，并为人类基因表达的表观遗传调控机制提供重要的见解。原子分辨结构也可用于辅助开发抗癌的治疗剂。

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.