RNA and Chromatin Formation: From Discovery to Mechanism

RNA 和染色质形成：从发现到机制

• 批准号: 7852410
• 负责人: John Louis Rinn
• 金额: $ 62.16万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852410
• 关键词: Address; Biology; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Code; DNA Methylation; Disease; Epigenetic Process; Functional RNA; Genome; Genomics; Goals; Health; Human; Maintenance; Malignant Neoplasms; Play; RNA; Regulation; Research; Role; Site; Therapeutic; Untranslated RNA; abstracting; base; genome-wide; histone modification; human disease; innovation; novel; public health relevance

DESCRIPTION (Provided by the applicant) Abstract: A major outstanding challenge in biology is to understand how the exact same genomic sequence present in every cell takes on alternate epigenetic landscapes to confer a myriad of cellular functions, all while using ubiquitous cellular machinery. In addition to histone modifications and DNA methylation, RNA has been long thought to be involved in the establishment and inheritance of these epigenetic states, but is far less understood. Indeed, recently three examples of large non-coding RNAs (HOTAIR, XIST and AIR) have been discovered that share a common theme: they physically associate with chromatin remodeling complexes and are required to guide chromatin formation at specific genomic loci. Although these examples suggest a general mechanism it is still unclear to what extent RNA plays a role in chromatin formation and the mechanisms by which this guidance occurs. Here we propose to comprehensively and systematically address the roles of large non-coding RNAs in the formation of chromatin structure. We will accomplish this by : (1) Identifying and characterize large noncoding RNAs that physically associate with chromatin remodeling complexes genome-wide across multiple yet related cell contexts; (2) Define the sites of regulations and the guidance mechanism to these genomic loci (3) Identify how these molecules and their mechanisms are misregulated in human disease. Together, our multifaceted experimental and computational approaches aim to 'crack the code' of epigenetic establishment and maintenance. This will transform our understanding of genome regulation and establish a new paradigm for RNA in the guidance of chromatin formation. Public Health Relevance: Our research aims to understand a universal problem in human health: How does the same genome present in every cell take on alternate identities that orchestrate distinctive cell states and how are these states misregulated in diseases such as cancer. We recently discovered a novel class of large intergenic non-coding RNAs (lincRNAs) that have the ability to regulate cellular identity and are misregulated in human cancers. Thus, we seek to establish the fundamental principles and mechanisms by which lincRNAs regulate cellular identity and their role in human cancers. The ultimate goal of these innovative experimental and computational approaches is to develop novel RNA based cancer therapeutics.

描述（由申请人提供） 摘要：生物学中一个主要的突出挑战是了解每个细胞中存在的完全相同的基因组序列如何在使用无处不在的细胞机制的同时呈现交替的表观遗传景观以赋予无数的细胞功能。除了组蛋白修饰和DNA甲基化之外，RNA长期以来一直被认为参与这些表观遗传状态的建立和遗传，但了解得很少。事实上，最近已经发现了三个大型非编码RNA（HOTAIR，XIST和AIR）的例子，它们有一个共同的主题：它们与染色质重塑复合物物理相关，并需要在特定的基因组位点引导染色质形成。虽然这些例子表明了一个一般的机制，但仍然不清楚RNA在染色质形成中发挥作用的程度以及这种指导发生的机制。在这里，我们建议全面和系统地解决大型非编码RNA在染色质结构形成中的作用。我们将通过以下方式实现这一目标：（1）在多个相关的细胞环境中识别和表征与全基因组染色质重塑复合物物理相关的大型非编码RNA;（2）定义这些基因组位点的调控位点和指导机制（3）确定这些分子及其机制如何在人类疾病中被错误调控。总之，我们多方面的实验和计算方法旨在“破解密码”的表观遗传的建立和维护。这将改变我们对基因组调控的理解，并为RNA指导染色质形成建立新的范式。 公共卫生相关性：我们的研究旨在了解人类健康中的一个普遍问题：存在于每个细胞中的相同基因组如何呈现出不同的身份，从而协调不同的细胞状态，以及这些状态如何在癌症等疾病中被错误调节。我们最近发现了一类新的大型基因间非编码RNA（lincRNA），它们具有调节细胞身份的能力，但在人类癌症中被错误调节。因此，我们寻求建立lincRNA调节细胞身份及其在人类癌症中的作用的基本原则和机制。这些创新的实验和计算方法的最终目标是开发新的基于RNA的癌症治疗方法。