Taming of Small RNA-based Epigenetic Mechanisms

驯服基于小RNA的表观遗传机制

• 批准号: 7981624
• 负责人: ALEXEI A. ARAVIN
• 金额: $ 243万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981624
• 关键词: Achievement; Affect; Attention; Cells; Chromatin; Critical Pathways; DNA Methylation; DNA Sequence; Development; Epigenetic Process; Gene Expression; Genetic; Goals; Investigation; Maintenance; Mediating; Medical; Medicine; Methodology; Methods; Pathway interactions; Phenotype; Play; Process; Regulation; Role; Science; Small RNA; Specificity; Stem cells; abstracting; base; cancer therapy; cancer type; genome-wide; innovation; insight; programs; stem cell technology; tool

DESCRIPTION (Provided by the applicant) Abstract: Epigenetics is defined as heritable changes in cellular and organismal phenotypes that do not alter the underlying genetic information. In recent years, epigenetic regulation has attracted much attention because it lies at the core of various pathways critical for normal development and pathological progression. Epigenetic processes are especially important for the maintenance of stem cells and their differentiated progenies, as well as for the initiation and pathological progression of various cancer types. Robust methods are available to detect epigenetic states on a genome-wide scale, but there is no reliable method to specifically manipulate them. Although the field of epigenetics has traditionally focused on DNA methylation and chromatin changes, other cellular mechanisms also play important roles in controlling stable switches between various cell fates. Here I propose an innovative approach to program intrinsic small RNA pathways to experimentally affect epigenetic states. I will study how small RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes with the ultimate goal of developing small RNA-based tools and methodologies to direct and maintain cellular fates. I will also investigate the crosstalk between small RNA- mediated processes and chromatin-based pathways with the goal of using small RNAs to induce chromatin changes at a specific locus. Investigation of RNA-based epigenetic mechanisms will further our understanding of how cellular fates are selected and fixed during normal development. The methods developed will allow modulation of cellular states with precision and specificity while preserving the underlying DNA sequence. Achievement of these goals will be of great importance for both general science and medicine, as these results will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications of stem cell technologies and anti-cancer therapies. Public Health Relevance: I will study how the small RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes, with the ultimate goal of developing tools and methodologies to direct and maintain cellular fates. Achievement of these goals will be of great importance for both general science and medicine, as it will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications, such as stem cell technologies and anti-cancer therapy.

描述（申请人提供） 摘要：表观遗传学被定义为不会改变潜在遗传信息的细胞和有机表型的可遗传变化。近年来，表观遗传调节引起了很多关注，因为它是对正常发育和病理进展至关重要的各种途径的核心。表观遗传过程对于维持干细胞及其分化的后代以及各种癌症类型的起始和病理进展尤为重要。强大的方法可用于以全基因组量表检测表观遗传状态，但是没有可靠的方法可以专门操纵它们。尽管表观遗传学领域传统上关注DNA甲基化和染色质的变化，但其他细胞机制在控制各种细胞命运之间的稳定开关方面也起着重要作用。在这里，我提出了一种创新的方法来编程内在的小RNA途径，以实验影响表观遗传状态。我将研究如何对小小的RNA途径进行编程以调节基因表达并引起可遗传的表型变化，这是开发基于RNA的小工具和方法的最终目标，以指导和维持细胞命运。我还将研究小RNA介导的过程和基于染色质的途径之间的串扰，目的是使用小RNA在特定基因座处诱导染色质变化。对基于RNA的表观遗传机制的研究将进一步了解我们对在正常发育过程中如何选择和固定细胞命运的理解。开发的方法将允许在保留潜在的DNA序列的同时，以精度和特异性调节细胞状态。实现这些目标对于一般科学和医学都将非常重要，因为这些结果将为开发和血统承诺的过程提供见解，并允许在干细胞技术和抗癌疗法的医疗应用中取得重大进展。 公共卫生相关性：我将研究如何对小的RNA途径进行编程以调节基因表达并引起可遗传的表型变化，这是开发工具和方法论以指导和维持细胞命运的最终目标。实现这些目标对于一般科学和医学将非常重要，因为它将提供有关发展和血统承诺过程的见解，并允许在医疗应用中取得重大进展，例如干细胞技术和抗癌治疗。