Transgenerational gene silencing

摘要 在许多国家，已经报道了可以持续许多代而不改变DNA序列的变化。 有机体人类也声称存在这种可遗传的表观遗传变化， 比如饥饿和心理创伤。然而，有穷人 理解在任何情况下表观遗传变化跨代持续存在的机制基础， 有机体虽然已经在多个系统中鉴定了介导这种变化的分子（例如，DNA 甲基化、染色质修饰、小RNA等），这些分子和化学物质的存在 修饰不能预测任何新引入的表观遗传变化的持续性。最近的概念 提供系统水平遗传理解的进展表明，调节结构的变化 驱动和维持可遗传的表观遗传变化。因此，关注监管架构可以揭示 解释任何可能持续多代人的变化所需的重要相互作用， 调节这些相互作用的特定分子。线虫C.多种现象 据报道，RNA介导的调节用于维持基因表达的沉默， 数百代人。因此，这些现象为分析遗传性表观遗传提供了机会 单基因分辨率的变化来获得洞察力。除了预期的广泛适用性的见解， 调节结构，甚至一些用于调节遗传表观遗传变化的特定分子， C. elegans，如piRNA、相分离的RNA颗粒、双链RNA导入物SID-1，以及 小RNA结合的Argonaute蛋白在包括人类在内的许多生物体中是保守的。我们的初步 结果揭示了一种促进模型稳定RNA沉默的调控结构 编码荧光蛋白的转基因和内源基因，这些基因对遗传易感性相似。 基因表达的表观遗传变化。本研究的目的是：（1）分析模式基因， 促进跨代基因沉默的调控序列和扰动;以及（2）分析 内源性基因的调控，以阐明调控结构，已演变为控制遗传 生殖系内基因表达的表观遗传变化。这些目标的实现将为我们提供一个 任何基因的遗传表观遗传变化的观点，并揭示了进化机制的调控结构。 这些结果将使人们更好地了解遗传性疾病，特别是可能具有遗传性的疾病。 一种早期的表观遗传起源。

Abstract Changes that can persist for many generations without altering DNA sequence have been reported in many organisms. The existence of such heritable epigenetic changes has also been claimed in humans in response to some stressful experiences such as starvation and psychological trauma. However, there is poor understanding of the mechanistic basis for the persistence of epigenetic changes across generations in any organism. Although molecules mediating such changes have been identified in multiple systems (e.g., DNA methylation, chromatin modifications, small RNAs, etc.), the mere presence of these molecules and chemical modifications do not predict the persistence of any newly introduced epigenetic change. Recent conceptual advances that provide a system-level understanding of heredity suggest that changes in regulatory architectures drive and maintain heritable epigenetic changes. Therefore, focusing on the regulatory architectures can reveal the important interactions required for explaining any change that can last for multiple generations regardless of the particular molecules that mediate these interactions. In the nematode C. elegans, multiple phenomena have been reported whereby RNA-mediated regulation is used to sustain the silencing of gene expression for hundreds of generations. These phenomena thus provide opportunities for analyzing heritable epigenetic changes at single-gene resolution to gain insights. In addition to the expected broad applicability of insights into regulatory architectures, even some of the specific molecules used to regulate heritable epigenetic changes in C. elegans such as piRNAs, phase-separated RNA granules, the double-stranded RNA importer SID-1, and small RNA-bound Argonaute proteins are conserved in many organisms, including humans. Our preliminary results have revealed insights into a regulatory architecture that promotes stable RNA silencing of a model transgene encoding a fluorescent protein and endogenous genes that are similarly susceptible to heritable epigenetic changes in gene expression. The aims of this proposal are: (1) to analyze model genes to discover the regulatory sequences and perturbations that promote transgenerational gene silencing; and (2) to analyze regulation of endogenous genes to elucidate the regulatory architectures that have evolved to control heritable epigenetic changes in gene expression within the germline. Completion of these goals will provide both a general view of heritable epigenetic changes at any gene and reveal the regulatory architecture of evolved mechanisms. These results will provide a better understanding of hereditary diseases, particularly diseases that could have an epigenetic origin in earlier generations.