Molecular Genetic Analysis of Extracellular RNAs in C. Elegans

项目摘要 基于他们从父母那里继承的基因，兄弟姐妹之间的相似程度超出了预期。这 一项意外的发现来自最近的研究，这些研究衡量了基因和基因之间的关联(基因变异 (DNA序列)和特征(例如身高或疾病风险)在大量无关人群中。这 差异表明父母可能会将额外的、非基因的信息传递给他们的后代。这种非基因 信息被称为表观遗传学，字面意思是“超越”遗传学，是一个久负盛名的领域，但却是惯例。 接受表观遗传信息每一代都会被抹去的观点。新兴领域的研究 跨代表观遗传(TEI)正在挑战这一传统。然而，人们对此知之甚少 关于遗传的表观遗传信息是如何编码的，它如何对环境条件做出反应，以及它如何 在几代人之间传递。因为遗传的表观遗传信息是可塑性的，可能解释了 高达一半的疾病风险遗传，这些问题的答案将对 社会和医学。 调查TEI是如何建立、维护和传播的是具有挑战性的：它需要分析 到目前为止，多代人和研究表明，它的影响是非永久性的，随着 几代人。这项拟议的研究使用线虫线虫来调查TEI。秀丽线虫有 研究TEI有许多实验优势，其中最主要的是快速、三天的生成时间 以及一种名为RNA干扰(RNAi)的强大分子工具，它可以指导任何基因的沉默。一 线虫中RNAi的特殊特征是沉默信号，RNA的一种形式，可以在 细胞和组织，包括生殖系，从而将沉默传递给后代。已发表的研究 来自申请者小组描述了TEI的RNAi依赖机制，表明表观遗传学 沉默可以维持近20代。为了进一步探讨TEI在C.Ti中的传播。 申请人建议(目标1)研究运输RNA的蛋白质的活性和选择性 细胞之间；(目标2)表征内源移动RNA的生物发生和运输，并 调查它们在表观遗传中的作用；和(目标3)调查患病率、机制和 TEI在生物体适应环境变化方面的效用。

Project Summary Siblings resemble each other more than expected based on the genes that they inherit from their parents. This unexpected finding derives from recent studies that measure the association between genotype (variations in DNA sequence) and traits (e.g. height or disease risk) among large populations of unrelated people. This discrepancy indicates that parents may transmit extra, non-gene, information to their offspring. This non-gene information is called epigenetics, literally “beyond” genetics, and is a well-established field, but convention accepts that epigenetic information is erased each generation. Studies in the emerging field of transgenerational epigenetic inheritance (TEI) are challenging this convention. However, little is known about how inherited epigenetic information is encoded, how it responds to environmental conditions, and how it is transmitted between generations. Because inherited epigenetic information is malleable and may account for up to half the inheritance of disease risk, the answers to these questions will have an enormous impact on society and medicine. Investigating how TEI is established, maintained, and transmitted is challenging: it requires analysis of multiple generations and studies to date indicate that its effects are impermanent, fading with successive generations. The proposed research uses the nematode C. elegans to investigate TEI. C. elegans has numerous experimental advantages for studying TEI, primary among them is a fast, three-day, generation time and a powerful molecular tool called RNA interference (RNAi), which can direct the silencing of any gene. One special characteristic of RNAi in C. elegans is that the silencing signals, a form of RNA, can move between cells and tissues, including to the germline, thus transmitting silencing to future generations. Published studies from the applicants group characterized an RNAi-dependent mechanism of TEI, showing that epigenetic silencing could be maintained for nearly 20 generations. To further explore the transmission of TEI in C. elegans the applicant proposes (Aim 1) to investigate the activity and selectivity of proteins that transport RNA between cells; (Aim 2) to characterize the biogenesis and transport of endogenous mobile RNAs and to investigate their role in epigenetic inheritance; and (Aim 3) to investigate the prevalence, mechanisms, and utility of TEI for organismal adaption to environmental change.