Identification and Characterization of Systems that Limit Transgenerational Epigenetic Inheritance (TEI)

项目摘要/摘要 在上个世纪的大部分时间里，人们认为生殖细胞中的所有表观遗传信息在一开始就被抹去了 每一代新一代。然而，现在人们知道，情况并不总是如此。许多例子表明 逃避重新编程和跨越代际界限的表观遗传信息现在已经 记录在案(统称为跨代表观遗传或TEI)。TEI的例子包括 植物中的参数转换，线虫中的RNAi遗传，以及小鼠获得性特征的遗传。给定 现在已经观察到了大量的TEI病例，TEI可能是一个重要的 适应性过程对我们对遗传的理解具有重要的影响。 我们还不知道表观遗传信息是如何遗传的，TEI是如何被调控的，或者为什么动物 拥有TEI系统。TEI的一个戏剧性的例子出现在模式生物秀丽线虫中：在线虫中， 双链(DS)RNA暴露(称为RNA干扰，RNAi)的影响可以从父母那里传递 传五代以上的后代(称为RNAi遗传)。我假设线虫拥有 限制TEI继承的系统，通过移除这些限制系统，TEI可能会持续更多代 比往常更好。考虑到这个想法，我进行了一次正向基因筛查，以确定导致RNAi的突变 继承的世代比正常情况下要多。我的屏幕鉴定了RNAi 1的基因可遗传增强子 (Heri-1)。HERI-1编码一个基因，其蛋白产物包含两个保守的结构域：一个推定的 染色域和与激酶同源的结构域。我发现HERI-1被招募到基因组位置 RNAi靶向和Heri-1在这些位点的招募限制了表观遗传信息的遗传 这些网站。据我所知，Heri-1是第一个致力于调节TEI的已知因子。 动物。 这里提出的研究策略旨在进一步洞察表观遗传是如何产生的 受监管的。目前，关于表观遗传信息是否可以 人类的遗传以及是否遗传的表观遗传信息可能会导致人类疾病。如果 这个问题的答案是肯定的，我探索TEI如何受到监管的工作可能会帮助我们 了解限制和调节表观遗传的基本分子机制，从而使 有可能以减轻人类疾病的方式影响可遗传的表观遗传过程。

PROJECT SUMMARY/ABSTRACT For most of the last century, it was thought that all epigenetic information in germ cells was erased at the start of each new generation. However, it is now known that this is not always the case. Many examples of epigenetic information escaping reprogramming and crossing generational boundaries have now been documented (collectively termed transgenerational epigenetic inheritance or TEI). Examples of TEI include paramutation in plants, RNAi inheritance in C. elegans, and the inheritance of acquired traits in mice. Given the large number of cases of TEI that have now been observed, it is possible that TEI may be an important adaptive process with significant implications for our understanding of heredity. We do not yet understand how epigenetic information is inherited, how TEI is regulated, or why animals possess TEI systems. One dramatic example of TEI occurs in the model organism C. elegans: in C. elegans, the effects of double stranded (ds)RNA exposure (termed RNA interference, RNAi) can be passed from parent to progeny for more than five generations (termed RNAi inheritance). I hypothesized that C. elegans possess systems that limit TEI inheritance and by removing these limiting systems, TEI might last for more generations than usual. With this idea in mind, I performed a forward genetic screen to identify mutations that make RNAi inheritance last for more generations than normal. My screen identified the gene heritable enhancer of RNAi 1 (heri-1). heri-1 encodes a gene whose protein product contains two conserved domains: a putative chromodomain and a domain with homology to kinases. I have found that HERI-1 is recruited to genomic sites targeted by RNAi and the recruitment of HERI-1 to these sites limits the inheritance of epigenetic information at these sites. As far as I am aware, HERI-1 represents the first known factor dedicated to the regulation of TEI in animals. The research strategy proposed here is designed to provide further insights into how epigenetic inheritance is regulated. There is currently intense scientific debate about whether or not epigenetic information can be inherited in humans and whether or not inherited epigenetic information might contribute to human disease. If the answer to this question turns out to be yes, my work exploring how TEI is regulated could help us understand the basic molecular mechanisms that limit and regulate epigenetic inheritance and, thus, make it possible to influence heritable epigenetic processes in such a way as to mitigate human disease.