RNA-mediated recruitment of epigenetic regulators

描述(由申请人提供)：建立和维持有丝分裂和减数分裂稳定的、表观遗传的基因表达模式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指导表观遗传学的调控机制，作为开发检测和减轻表观遗传学疾病的诊断和治疗分析的先决条件。这项拟议的研究背后的具体假设是，表观遗传调控因子的目标基因转录非编码RNA，该非编码RNA结合并招募表观遗传调控因子。这一假说是基于以下观察结果：1)表观遗传调节因子(TrE和前元件)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由TrE或前元件转录的RNA相互作用，以及3)TrE和前元件的瞬时转录恢复了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，这一提议的实验重点是非编码RNA在招募表观遗传调控因子以靶向基因方面的作用。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。我们将确定介导从tre-和前元件转录的RNA与表观遗传调节因子相互作用的蛋白质和RNA基序，以及将RNA保留在tre-和前元件的蛋白质。 2.确定表观遗传调节子与tre和前转录产物之间的新的相互作用。TrE-和Pre-元件是各种表观遗传调节因子的靶标，这意味着来自这些元件的RNA可能会招募不同表观遗传调节因子家族的成员。我们将确定表观遗传调控因子与从TrE-和Pre-元素转录的RNA之间的新的相互作用。 3.剖析表观遗传和非编码RNA相互作用在发育和疾病中的作用和功能。招募表观遗传调节者来靶向基因与发育和疾病相关。我们将把细胞和组织中来自tre-和pre-元件的RNA转录与表观遗传调节因子对靶基因的招募、果蝇细胞命运的决定以及哺乳动物细胞的异常增殖联系起来。

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.