Non-Coding RNAs in Gene Regulation, Genome Defense, and Epigenetic Inheritance

项目摘要/摘要 表观遗传系统调节生殖和发育过程中的基因表达，以及 这些途径会导致疾病。非编码RNA是表观遗传的主要调节者和协调者 在所有真核生物中的过程。例如，非编码的RNA指导植物中的参数突变，异染色质 酵母菌的形成，草履虫的基因组重排，以及X染色体的失活和印记 哺乳动物。此外，虽然大多数表观遗传信息每一代都会被擦除，以确保 生殖系的全能性，在某些情况下，表观遗传信息逃脱重新编程并传递 世代遗传(称为跨代表观遗传或TEI)。目前的证据表明，非 编码RNA是植物、蠕虫、昆虫，可能还有哺乳动物中TEI的主要信息载体。这个 我的研究计划的长期目标是了解非编码RNA如何调节和塑造基因 在某些情况下，表达程序和这种监管是如何代代相传的。 我们正在使用后生动物模式生物秀丽线虫来解决这些问题。来确定我们的工作的日期 已经确定了rna干扰(RNAi)途径的一个核分支，它使用小干扰(Si)rna。 调节染色质状态，抑制RNAP II延长。我们还确定了路径和系统 在世代之间传递表观遗传信息所需的。我们最近的研究发现了一种新的 一种无膜细胞器，含有TEI所需的蛋白质，确定了两种天然的作用途径 在TEI上的断裂，并定义了一种由一种新形式的RNA修饰介导的TEI的潜在机制 我们帮助发现了。因为我们发现转座子是线虫的主要靶标 表观遗传途径，我们推测非编码RNA和TEI系统的一个功能是帮助 给后代接种对抗核酸寄生虫表达的疫苗。 表观遗传途径的解除管制导致了许多人类疾病的病因学。这个 在所有真核生物中，非编码RNA和表观遗传过程之间存在广泛的联系，这表明 我们在线虫上所做的工作将带来适用于所有动物的见解，因此可能会有所帮助 美国人了解和治疗人类的疾病。

PROJECT SUMMARY / ABSTRACT Epigenetic systems regulate gene expression during reproduction and development and the misregulation of these pathways leads to disease. Non-coding RNAs are major regulators and orchestrators of epigenetic processes in all eukaryotes. For instance, non-coding RNA directs paramutation in plants, heterochromatin formation in yeast, genome rearrangement in paramecium, and X-chromosome inactivation and imprinting in mammals. Additionally, while most epigenetic information is erased each and every generation to ensure totipotency of the germline, in some cases, epigenetic information escapes reprogramming and passes across generations (termed transgenerational epigenetic inheritance or TEI). Current evidence suggests that non- coding RNAs are major informational vectors for TEI in plants, worms, insects, and, possibly, mammals. The long-term goal of my research program is to understand how non-coding RNA regulates and sculpts gene expression programs and how this regulation is, in some cases, passed across generations. We are using the metazoan model organism C. elegans to address these questions. To date our work has identified a nuclear branch of the RNA interference (RNAi) pathway, which uses small interfering (si)RNAs to regulate chromatin states and inhibit RNAP II elongation. We have also identified pathways and systems required for transmission of epigenetic information across generations. Our recent studies have identified a new type of membraneless organelle that houses proteins needed for TEI, identified two pathways that act as natural breaks on TEI, and defined an underlying mechanism for TEI mediated by a new form of RNA modification that we helped discover. And because we find that transposable elements are a major target of the C. elegans epigenetic inheritance pathways, we theorize that one function of non-coding RNAs and TEI systems is to help inoculate progeny against the expression of nucleic acid parasites. Deregulation of epigenetic pathways contributes to the etiology of a number of human diseases. The extensive links existing between non-coding RNA and epigenetic processes in all eukaryotes suggests that the work we are doing in C. elegans will lead to insights that will be applicable to all animals and, therefore may help us understand and treat disease in people.