Molecular Genetic Analysis of Extracellular RNAs in C. Elegans

项目摘要 根据它们从父母那里继承的基因，它们彼此之间的相似程度比预期的要高。这 一个意想不到的发现来自最近的研究，测量基因型之间的关联（变异， DNA序列）和性状（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信息传递给后代。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，是一个建立良好的领域，但公约 接受表观遗传信息在每一代都被抹去。新兴领域的研究 跨代表观遗传（TEI）正在挑战这一传统。然而， 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 是代代相传的因为遗传的表观遗传信息具有可塑性， 高达一半的遗传疾病风险，这些问题的答案将产生巨大的影响， 社会和医学。 调查TEI是如何建立、维护和传输的是一项挑战：它需要分析 多代人和迄今为止的研究表明，它的影响是暂时的，随着连续的 代这项研究利用线虫C. elegans来研究TEI。C. elegans有 研究TEI的许多实验优势，其中主要是快速，三天，世代时间 以及一种称为RNA干扰（RNAi）的强大分子工具，它可以指导任何基因的沉默。一 C. RNA干扰特性沉默信号是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。发表的研究 来自申请人组的2000人表征了TEI的RNAi依赖性机制，表明表观遗传 沉默可以维持近20代。进一步探讨TEI在C. 申请人提出（目的1）研究转运RNA的蛋白质的活性和选择性 （目的2）表征内源性移动的RNA的生物发生和转运， 研究它们在表观遗传中的作用;（目的3）研究它们的患病率、机制和 TEI在生物适应环境变化中的作用。

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.