Toward a Central Question in Epigenetics: A Major Epigenetic Programming Mechanis

表观遗传学的一个核心问题：主要的表观遗传编程机制

• 批准号: 7979406
• 负责人: Haifan Lin
• 金额: $ 82.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979406
• 关键词: Accounting; Binding; Biological Assay; Biomedical Research; Chromatin; Complex; Development; Dimensions; Drosophila genus; Epigenetic Process; Gene Targeting; Genes; Genetic; Genome; Genomics; Heterochromatin; Maps; Mediating; Molecular Genetics; Play; Proteins; Recruitment Activity; Regulation; Resolution; Role; Site; Testing; Work; abstracting; base; fascinate; frontier; genome-wide; piRNA; programs; promoter; stem cell biology

DESCRIPTION Abstract: Epigenetics represents an exciting new frontier of biomedical research. A central yet essentially unexplored question in epigenetics is how epigenetic regulators are directed to specific loci in the genome to exert their function. It is known that a few transcriptional factors can recruit certain epigenetic factors to the promoters of target genes. However, this mechanism so far can only account for a handful of genes, and a tiny fraction of the genome. The latest Drosophila work in my lab suggest that PIWI-interacting RNAs (piRNAs) play a major and direct role in guiding epigenetic factors to many sites in the genome. Particularly, piRNA form complexes with PIWI proteins and directly bind to piRNA-complementary sites in the genome to regulate their epigenetic state. Furthermore, we have shown that PIWI directly recruits a key epigenetic factor called Heterochromatin Protein 1a to these sites. Based on these results, we propose a "Piwi-piRNA guidance hypothesis", in which the Piwi-piRNA complex serves as a sequence- recognition machinery that recruits epigenetic effectors to specific genomic sites to execute epigenetic regulation. Here we propose to use combined genetic and genomic approaches to systematically test this hypothesis and to determine the contribution of the PIWI-piRNA- mediated mechanism to the genome at 10-basepair resolution. Specifically, we propose to: (1) Create the first functional epigenome map to determine the specific epigenetic effect of PIWI towards different regions of the genome; (2) develop a genome-wide epigenetic assay to examine the sufficiency and direct role of PIWI in regulating the transcriptional state of chromatin; and (3) take a four-pronged approach to directly test the role of piRNAs in guiding epigenetic factors to their sites. The proposed study should reveal a fascinating dimension of epigenetic regulation and generate a potentially transformative impact to the broad fields of epigenetics, genetics, molecular, develo

描述 抽象的： 表观遗传学代表了生物医学研究的一个令人兴奋的新领域。表观遗传学中一个核心但本质上尚未探索的问题是表观遗传调节因子如何定向到基因组中的特定位点以发挥其功能。已知一些转录因子可以将某些表观遗传因子招募到靶基因的启动子上。然而，到目前为止，这种机制只能解释少数基因和基因组的一小部分。我实验室最新的果蝇研究表明，PIWI 相互作用 RNA (piRNA) 在引导表观遗传因子到达基因组中的许多位点方面发挥着重要而直接的作用。特别是，piRNA 与 PIWI 蛋白形成复合物，并直接结合基因组中的 piRNA 互补位点来调节其表观遗传状态。此外，我们还发现 PIWI 直接将一种称为异染色质蛋白 1a 的关键表观遗传因子招募到这些位点。基于这些结果，我们提出了“Piwi-piRNA指导假说”，其中Piwi-piRNA复合物充当序列识别机制，将表观遗传效应子招募到特定基因组位点以执行表观遗传调控。在这里，我们建议使用组合的遗传和基因组方法来系统地检验这一假设，并以 10 碱基对分辨率确定 PIWI-piRNA 介导的机制对基因组的贡献。具体来说，我们建议：（1）创建第一个功能表观基因组图谱，以确定 PIWI 对基因组不同区域的特定表观遗传效应； (2) 开发全基因组表观遗传学检测，以检验 PIWI 在调节染色质转录状态中的充分性和直接作用； (3)采取四管齐下的方法直接测试piRNA在引导表观遗传因子到达其位点方面的作用。拟议的研究应该揭示表观遗传调控的一个令人着迷的维度，并对表观遗传学、遗传学、分子、开发等广泛领域产生潜在的变革性影响。