Small regulatory RNA functions in the nucleus

项目摘要 表观遗传学是研究基因表达或表型的变化，而这些变化不是变化的结果 在DNA序列中。RNA已成为指导许多表观遗传过程的重要信息载体。 此外，在上个世纪的大部分时间里，人们普遍认为（与遗传信息不同）表观遗传 信息没有跨越代际界限。换句话说，表观遗传信息被抹去， 每一代都是如此，以至于后代的生命开始于一个空白的表观遗传石板。现在知道这不是 总是这样。许多表观遗传信息跨代传递的例子现在已经被 记录在案。表观遗传信息的遗传超过一代被称为跨代 表观遗传（TEI）。非编码RNA，特别是小的非编码RNA，例如piRNA， 现在已经将miRNA、siRNA和tRNA与植物、蠕虫、昆虫和哺乳动物中的TEI相关联。因此，小 在许多真核生物中，非编码RNA是TEI的重要信息载体。 在大多数真核生物中，dsRNA诱导基因沉默（RNAi）。我们已经在C. elegans识别 将小的非编码RNA与转录调节偶联的因子。最近，这些研究使我们 发现了一种新型的沉默RNA，我们称之为pUG RNA。令人惊讶的是，C.优美的主题 对于RNAi来说，沉默RNAi靶向基因的能力遗传了许多代（5 - 10代）（称为RNAi遗传）。 因此，C.线虫是RNA指导的TEI的一个特别可靠的例子。我们还使用 C.线虫作为一个模型系统，探索RNA指导的机制基础， 动物中的TEI。我们正在使用遗传筛选来确定促进和限制TEI所需的细胞因子 以及生物化学和细胞生物学方法来探索这些因素如何驱动TEI。最后，我们还使用 这个系统来探索为什么动物有TEI系统摆在首位。 在许多非编码RNA和TEI过程之间的进化保守的连接， 不同的物种表明我们在C.优雅的人可能会带来对 TEI的机制，这将适用于一般的真核生物。表观遗传途径的错误调节 已知它与包括癌症在内的数十种人类疾病的病因有关。我们提出的工作将 可能会增加我们对RNA如何重新编程表观遗传状态的理解，因此可能有助于我们 了解并治疗这些疾病。此外，人们是否可以继承遗产的问题 来自父母的表观遗传信息是激烈的科学辩论的主题。如果人们真的能继承 从父母那里遗传了表观遗传信息那么他们就有可能遗传了错误的表观遗传信息 信息，这可能会导致疾病。我们对RNA介导的TEI机制的研究可能会使 有可能影响人们的TEI途径以减轻疾病。

PROJECT SUMMARY Epigenetics is the study of changes in gene expression or phenotypes that are not the result of changes in DNA sequence. RNA has emerged as an important informational vector directing many epigenetic processes. Additionally, for most of the last century it was widely believed that (unlike genetic information) epigenetic information did not pass across generational boundaries. In other words, epigenetic information was erased each and every generation such that offspring began life with a blank epigenetic slate. It is now known that this is not always the case. Many examples of the trans-generational transfer of epigenetic information have now been documented. The inheritance of epigenetic information for more than one generation is termed transgenerational epigenetic inheritance (TEI). Non-coding RNAs and, in particular, small non-coding RNAs such as piRNAs, miRNAs, siRNAs, and tRNAs have now been linked to TEI in plants, worms, insects, and mammals. Thus, small non-coding RNAs are important informational vectors for TEI in many eukaryotes. In most eukaryotes, dsRNA induces gene silencing (RNAi). We have used RNAi in C. elegans to identify factors that couple small non-coding RNAs to transcriptional regulation. Recently, these studies led us to discover a new type of silencing RNA that we term the pUG RNA. Amazingly, progeny of C. elegans subjected to RNAi inherit the ability to silence RNAi-targeted genes for many (5-10) generations (termed RNAi inheritance). Thus, RNAi inheritance in C. elegans is a particular robust example of RNA-directed TEI. We are also using RNAi inheritance in C. elegans as a model system to explore the mechanistic underpinnings of RNA-directed TEI in animals. We are using genetic screens to identify cellular factors required for promoting and limiting TEI and biochemical and cell biological approaches to explore how these factors drive TEI. Finally, we are also using this system to explore why animals have TEI systems in the first place. The evolutionarily conserved connections between non-coding RNAs and TEI processes in many different species suggests that the work we are doing in C. elegans may lead to fundamental insights into mechanisms of TEI, which will be applicable to eukaryotes in general. The mis-regulation of epigenetic pathways is known to contribute to the etiology of dozens of human diseases, including cancer. Our proposed work will likely increase our understanding of how RNA reprograms epigenetic states and, therefore, may help us understand and, possibly, treat these diseases. Additionally, the question of whether or not people can inherit epigenetic information from their parents is the subject of intense scientific debate. If people can indeed inherit epigenetic information from their parents then it stands to reason they could inherit the wrong epigenetic information, which might predispose to disease. Our work exploring mechanisms of RNA-directed TEI may make it possible to influence TEI pathways in people to mitigate disease.