RNA-mediated recruitment of epigenetic regulators

RNA介导的表观遗传调节因子的募集

• 批准号: 7033046
• 负责人: FRANK U SAUER
• 金额: $ 28.17万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033046
• 关键词: Drosophilidae; RNA; RNA binding protein; RNA interference; cell proliferation; genetic disorder; genetic regulation; genetic regulatory element; mass spectrometry; nucleic acid structure; protein structure function; recombinant proteins; small interfering RNA

DESCRIPTION (provided by applicant): The establishment and maintenance of mitotically and meitotically stable, epigenetic, gene expression patterns are the hallmark of cell fate determination in metazoans and mistakes in the underlying mechanisms can result in cancerous cell growth. Our long-term goal is to elucidate the regulatory mechanisms directing epigenetic as a prerequisite for the development of diagnostic and therapeutic assays that detect and attenuate epigenetic-based diseases. The specific hypothesis behind the proposed research is that the target genes of epigenetic regulators transcribe non-coding RNA that bind and recruit epigenetic regulators. That hypothesis is based on the observations that 1) DMA elements targeted by epigenetic regulators (TRE-and-PRE-elements) are transcribed in vivo, 2) epigenetic regulators of the SET-module family interact with RNA transcribed from TRE- or PRE-elements, and 3) the transient transcription of TRE- and PRE-elements restores the interaction of epigenetic regulators with target genes in vivo. Based on these observations, the experimental focus of this proposal is on the role of non-coding RNA for the recruitment of epigenetic regulators to target genes. The specific aims are to: 1. Elucidate the role of non-coding RNA for the recruitment of epigenetic regulators. We will identify the protein- and RNA-motifs that mediate the interaction of RNA transcribed from TRE- and PRE-elements with epigenetic regulators and proteins that retain the RNA at TRE- and PRE-elements. 2. Identify novel interactions between epigenetic regulators and TRE- and PRE-transcripts. TRE- and PRE-elements serve as a target for various groups of epigenetic regulators, implying that RNA from those elements may recruit members of different families of epigenetic regulators. We will identify novel interactions between epigenetic regulators and RNA transcribed from TRE- and PRE-elements. 3. Dissection of the role and function of the interaction between epigenetic and non-coding RNA for development and disease. The recruitment of epigenetic regulators to target genes correlates with development and disease. We will correlate the transcription of RNA from TRE- and PRE-elements in cells and tissues with the recruitment of epigenetic regulators to target genes, cell fate determination in Drosophila, and the aberrant proliferation of mammalian cells.

描述（由申请人提供）：有丝分裂和减数分裂稳定、表观遗传、基因表达模式的建立和维持是后生动物细胞命运决定的标志，潜在机制的错误可能导致癌细胞生长。我们的长期目标是阐明表观遗传的调控机制，作为开发检测和减轻表观遗传疾病的诊断和治疗方法的先决条件。这项研究背后的具体假设是表观遗传调节因子的靶基因转录非编码RNA，这些RNA结合并招募表观遗传调节因子。该假设基于以下观察结果：1) 表观遗传调节因子（TRE 和 PRE 元件）靶向的 DMA 元件在体内转录，2) SET 模块家族的表观遗传调节因子与 TRE 或 PRE 转录的 RNA 相互作用元件，3) TRE-和 PRE-元件的瞬时转录恢复表观遗传调节因子与体内靶基因的相互作用。基于这些观察，本提案的实验重点是非编码 RNA 在招募表观遗传调节因子到靶基因中的作用。具体目标是： 1. 阐明非编码RNA在表观遗传调控因子招募中的作用。我们将鉴定介导从 TRE 和 PRE 元件转录的 RNA 与表观遗传调节因子和在 TRE 和 PRE 元件处保留 RNA 的蛋白质相互作用的蛋白质和 RNA 基序。 2. 确定表观遗传调节因子与 TRE 和 PRE 转录本之间的新相互作用。 TRE-和PRE-元件作为不同组表观遗传调节因子的靶标，这意味着来自这些元件的RNA可能招募不同表观遗传调节因子家族的成员。我们将鉴定表观遗传调节因子与 TRE 和 PRE 元件转录的 RNA 之间的新相互作用。 3. 剖析表观遗传和非编码RNA之间相互作用对发育和疾病的作用和功能。表观遗传调节因子对靶基因的募集与发育和疾病相关。我们将把细胞和组织中 TRE 和 PRE 元件的 RNA 转录与靶基因表观遗传调节因子的招募、果蝇中的细胞命运决定以及哺乳动物细胞的异常增殖联系起来。