RNA-mediated recruitment of epigenetic regulators

描述（由申请人提供）：有丝分裂和减数分裂稳定的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指导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。拟议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：1）表观遗传调节因子靶向的DMA元件（TRE-and-PRE-elements）在体内转录，2）SET-模块家族的表观遗传调节因子与从TRE-或PRE-elements转录的RNA相互作用，以及3）TRE-和PRE-elements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。基于这些观察结果，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在表观遗传调节因子募集中的作用。我们将确定的蛋白质和RNA基序，介导的RNA转录从TRE和PRE元件与表观遗传调节因子和蛋白质，保留在TRE和PRE元件的RNA的相互作用。 2.鉴定表观遗传调节因子与TRE-和PRE-转录本之间的新型相互作用。TRE-和PRE-元件作为各种组的表观遗传调节剂的目标，这意味着来自这些元件的RNA可以招募不同家族的表观遗传调节剂的成员。我们将确定新的表观遗传调节和RNA转录TRE和PRE元件之间的相互作用。 3.解剖表观遗传和非编码RNA之间的相互作用对发育和疾病的作用和功能。表观遗传调节因子向靶基因的募集与发育和疾病相关。我们将从TRE-和PRE-元件在细胞和组织中的RNA的转录与表观遗传调节剂的招募靶基因，果蝇细胞命运的决定，和哺乳动物细胞的异常增殖。

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.