Roles of Chromatin Protein HIM-17 in Chromosome Structure and Function

描述(由申请人提供)：拟议研究的长期目标是了解染色体和染色质结构如何控制基本的细胞过程。染色体和染色质结构的变化会影响DNA和染色质结合蛋白与其作用部位的结合能力，从而提供一种机制来调节转录、信号和基因组稳定途径。为了进一步了解这些基于染色体的调控机制，目前的应用将集中在线虫蛋白HIM-17上，这是一种染色质相关蛋白，被认为具有全球染色质组织者的功能。HIM-17是减数分裂染色体正确分离所必需的，这一过程的失败会导致非整倍体后代，这是人类流产和出生缺陷的主要原因之一。HIM-17还在维持生殖细胞增殖和分化之间的正确平衡方面发挥作用。如果不能保持这种平衡，就会导致肿瘤的形成和生长。最后，正常获得生殖系染色质的共价修饰需要HIM-17。拟议的实验将研究HIM-17与染色质相互作用以控制这些基本细胞过程的机制。其具体目的是：1)评估候选HIM-17相关蛋白在基因组稳定性、染色质甲基化以及调节生殖细胞增殖和分化之间的平衡中的作用；2)研究HIM-17、组蛋白甲基转移酶MET-2与生殖细胞染色质甲基化之间的关系；3)研究HIM-17作为肿瘤抑制蛋白的作用；以及4)进行筛选以确定与HIM-17合作或拮抗的基因产物。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand how chromosome and chromatin structures control essential cellular processes. Changes in chromosome and chromatin structures can affect the ability of DNA and chromatin binding proteins to associate with their sites of action, thereby providing a mechanism by which to regulate transcription, signaling, and genome-stability pathways. To further our understanding of these chromosome-based control mechanisms, the current application will focus on the C. elegans protein HIM-17, a chromatin-associated protein that is proposed to function as a global chromatin organizer. HIM-17 is required for proper segregation of meiotic chromosomes, a process whose failure leads to aneuploid offspring, one of the leading causes of miscarriages and birth defects in humans. HIM-17 also functions in maintaining the correct balance between proliferation and differentiation of germ cells. Failure to maintain this balance can result in the formation and growth of tumors. Finally, HIM-17 is required for normal acquisition of covalent modifications of germline chromatin. The experiments proposed will investigate the mechanisms by which HIM-17 interacts with chromatin to control these essential cellular processes. The specific aims are: 1) To assess candidate HIM-17-associated proteins for roles in genome stability, chromatin methylation, and regulating the balance between germ cell proliferation and differentiation, 2) To investigate relationships between HIM-17, histone methyltransferase MET-2, and chromatin methylation in germ cells, 3) To investigate the role of HIM-17 as a tumor suppressor protein, and 4) To conduct screens to identify gene products that collaborate with or antagonize HIM-17.