Structural Studies of Transcriptional Silencing

描述（由申请人提供）：基因表达的表观遗传控制在真核生物学中起重要作用。表观遗传调控的实例包括在发育期间和分化细胞中控制Hox基因表达、剂量补偿和衰老。许多癌症与改变的表观遗传调控有关，这涉及到更高级染色质结构的组装。该建议的重点是研究建立和维持高级染色质结构的分子机制。 我们使用X射线晶体学作为我们的主要工具来研究表观遗传调节剂被招募到沉默的基因组位点，组蛋白修饰酶的结构和功能，以及组蛋白代码的识别的机制。我们将同时研究S.酿酒酵母和染色质相关蛋白。这项研究应该提供异染色质组装在酵母的机制的理解，以及提供重要的见解，在人类基因表达的表观遗传调控机制。原子分辨率结构也可用于帮助开发针对癌症的治疗剂。

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.