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Targeting of Heterochromatin Assembly in Schizosaccharomyces pombe

粟酒裂殖酵母中异染色质组装的靶向

基本信息

批准号：
8052959
负责人：
THOMAS A VOLPE
金额：
$ 24.99万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Heterochromatin has been implicated in the regulation of a wide range of cellular processes including gene expression, chromosome segregation and cellular differentiation. The mechanisms involved in targeting heterochromatin to specific regions of the genome, however, are not fully understood. We gained insight into this problem when we found that double stranded RNA synthesized from heterochromatic centromeric sequences becomes rapidly processed by the RNAi machinery resulting in sequence specific targeting of heterochromatin to centromeres. The main goal of this proposal is to determine how specific regions of the genome become targeted for heterochromatin assembly. Our specific aims are to: 1) Identify the centromeric repeat sequences that are important for heterochromatin assembly. Although it is known that centromeric repeats are sufficient to recruit heterochromatin, precisely which of these centromeric sequences are important for heterochromatin assembly and how they function to recruit silencing is not clear. We will directly test this by assaying the ability of various centromeric repeat sequences to recruit heterochromatin assembly to an ectopic euchromatic site. 2) Determine whether RNA mediated heterochromatin formation normally occurs in cis or in trans. We will address whether the centromeric repeat sequences located at heterochromatic regions in fission yeast function to recruit heterochromatin assembly in cis or rather act as targets for heterochromatin targeting via silencing signals, such as centromeric small RNAs generated in trans. 3) Identify factors involved in initiation of heterochromatin assembly. In specific aim 3 we will use a combination of strategies to identify novel factors involved in initiation of heterochromatin assembly. It is important that heterochromatin be confined to discrete chromosomal regions since improper targeting of heterochromatin can lead to misregulation of gene expression and onset of human diseases such as cancer. Our studies may lead to the development of techniques that allow manipulation of heterochromatic domains which would be extremely useful not only as experimental tools to study gene function but also as potential treatments for human disease.

描述（由申请人提供）：异染色质参与多种细胞过程的调节，包括基因表达、染色体分离和细胞分化。然而，将异染色质靶向基因组特定区域的机制尚不完全清楚。当我们发现从异染色质着丝粒序列合成的双链 RNA 被 RNAi 机器快速加工，导致异染色质序列特异性靶向着丝粒时，我们深入了解了这个问题。该提案的主要目标是确定基因组的特定区域如何成为异染色质组装的目标。我们的具体目标是：1）鉴定对异染色质组装重要的着丝粒重复序列。尽管已知着丝粒重复足以招募异染色质，但这些着丝粒序列中的哪些对于异染色质组装非常重要以及它们如何发挥招募沉默的作用尚不清楚。我们将通过测定各种着丝粒重复序列将异染色质组装招募到异位常染色位点的能力来直接测试这一点。 2) 确定RNA介导的异染色质形成通常以顺式还是反式发生。我们将解决位于裂殖酵母异染色质区域的着丝粒重复序列是否起到顺式招募异染色质组装的作用，还是通过沉默信号（例如反式产生的着丝粒小RNA）作为异染色质靶向的靶标。 3) 确定参与异染色质组装启动的因素。在具体目标 3 中，我们将使用多种策略组合来识别参与异染色质组装启动的新因素。重要的是，异染色质仅限于离散的染色体区域，因为异染色质的不正确靶向可能导致基因表达的错误调节和癌症等人类疾病的发生。我们的研究可能会导致技术的发展，允许操纵异染色质域，这不仅非常有用作为研究基因功能的实验工具，而且作为人类疾病的潜在治疗方法。