Multi-Generational Epigenetic Inheritance and Germline Immortality

多代表观遗传和种系永生

• 批准号: 8966375
• 负责人: Scott G Kennedy
• 金额: $ 16.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-24 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966375
• 关键词: Multi; Generational; Epigenetic; Inheritance; Germline

DESCRIPTION (provided by applicant): Epigenetics is the study of changes in gene expression or phenotype that occur without associated changes in DNA sequence. Epigenetic processes drive and/or regulate a wide-variety of biological processes such as imprinting, X-chromosome inactivation, and paramutation. Epigenetic information can be inherited across generational boundaries. A particularly striking example of epigenetic inheritance is dsRNA mediated gene silencing (RNAi). In C. elegans gene the effects of RNAi can persist for more than ten generations; a process termed RNAi inheritance. The following questions concerning RNAi inheritance have not been answered. What is the molecular agent that drives RNAi inheritance? How are non-coding RNA- directed epigenetic "memories" maintained across generations? Are genes normally subjected to heritable epigenetic regulation during reproduction? If so, why? Our long-term goal is to answer these questions. Towards this goal, we have conducted a genetic screen in C. elegans designed to identify cellular factors specifically required for inheritance of dsRNA-mediated silencing signals. This screen identified at least four genes including the gene failure to inherit RNAi (finn)-1. finn-1 encodes an Argonaute (Ago) that associates with siRNAs, and promotes RNAi inheritance, in germ cells of the progeny of animals exposed to dsRNA. Under normal growth conditions, FINN-1 associates with endogenously expressed small RNAs, which direct chromatin modifications in germ cells. In animals lacking FINN-1, these chromatin marks are lost over generations, and, concomitantly, these animals become sterile due to multi-generational atrophy of the germline. These results establish that small RNAs, acting in conjunction with FINN-1, are required for RNAi inheritance and germline immortality. In this proposal, we seek to identify additional components of the RNAi inheritance machinery and explore in more detail how FINN-1 and small regulatory RNAs direct RNAi inheritance and germline immortality. Our experiments are revealing how and why non-coding RNAs drive epigenetic inheritance. Non-coding RNAs are associated with a diverse array of epigenetic phenomena. Therefore, we believe that insights from our research will prove to be globally applicable to our understanding of epigenetic inheritance in animals. In addition, mis-regulation of epigenetic pathways in humans contributes to disease. Thus, the knowledge we provide might make it possible to influence epigenetic processes with the goal of mitigating human disease.

描述（由申请人提供）：表观遗传学是对基因表达或表型变化的研究，而DNA序列没有相关的变化。表观遗传过程驱动和/或调节各种各样的生物过程，如印迹、x染色体失活和参数化。表观遗传信息可以跨代遗传。表观遗传的一个特别显著的例子是dsRNA介导的基因沉默（RNAi）。在秀丽隐杆线虫基因中，RNAi的作用可以持续十代以上；这个过程被称为RNAi遗传。以下关于RNAi遗传的问题还没有得到解答。驱动RNAi遗传的分子因子是什么？非编码RNA导向的表观遗传“记忆”是如何跨代维持的？在繁殖过程中，基因是否通常受到可遗传的表观遗传调控？如果是，为什么？我们的长期目标是回答这些问题。为了实现这一目标，我们在秀丽隐杆线虫中进行了遗传筛选，旨在确定dsrna介导的沉默信号遗传特异性所需的细胞因子。该筛选至少鉴定了四个基因，包括遗传RNAi (finn)-1失败的基因。fin -1编码与sirna相关的Argonaute (Ago)，并在暴露于dsRNA的动物后代的生殖细胞中促进RNAi遗传。在正常生长条件下，FINN-1与内源性表达的小rna结合，指导生殖细胞的染色质修饰。在缺乏fin -1的动物中，这些染色质标记在几代中丢失，同时，由于生殖系的多代萎缩，这些动物变得不育。这些结果表明，与fin -1一起作用的小rna是RNAi遗传和种系不朽所必需的。在本提案中，我们试图确定RNAi遗传机制的其他组成部分，并更详细地探索fin -1和小调控rna如何直接RNAi遗传和种系不朽。我们的实验揭示了非编码rna驱动表观遗传的方式和原因。非编码rna与多种表观遗传现象有关。因此，我们相信我们研究的见解将被证明是全球适用于我们对动物表观遗传的理解。此外，人类表观遗传途径的错误调控也会导致疾病。因此，我们提供的知识可能会影响表观遗传过程，以减轻人类疾病的目标。