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、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学的调控机制，作为发展诊断和治疗检测和减轻基于表观遗传学的疾病的先决条件。提出的研究背后的具体假设是，表观遗传调控因子的靶基因转录非编码RNA，结合并招募表观遗传调控因子。该假设基于以下观察结果：1)表观遗传调控因子靶向的DMA元件（tret和PRE-elements）在体内转录；2)set模块家族的表观遗传调控因子与TRE-或PRE-elements转录的RNA相互作用；3)TRE-和PRE-elements的瞬时转录恢复了表观遗传调控因子与靶基因在体内的相互作用。基于这些观察结果，本研究的实验重点是非编码RNA在表观遗传调控因子招募靶基因中的作用。具体目标是：

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.