Elucidating the structure and function of non-coding RNA - LSD1 interactions

该研究项目的核心假设是核糖核酸（RNA）结构 RNA-染色质相关蛋白相互作用在维持 基因组稳定性非编码RNA（ncRNA）是基因表达的关键调控因子， 表达，并且已知与染色质相关蛋白物理结合， 在细胞的特定发育阶段组织基因结构的变化。一 这些RNA-蛋白质相互作用的子集与衰老、癌症转移和 神经元发育随着基因组方法开始鉴定RNA蛋白 协会及其与癌症的联系，仍然有有限的信息， 在分子水平上的基于表观遗传的RNA结合蛋白。我们寻求理解 RNA如何与赖氨酸特异性脱甲基酶-1（LSD 1）蛋白功能性相互作用 酵素LSD 1是一种重要的组蛋白甲基化调节剂，具有致癌作用。 在几种癌症中的特性，包括：前列腺癌、膀胱癌、神经母细胞瘤、肺癌和 乳腺癌LSD 1通过其庞大的相互作用网络与癌症有关。LSD1 也与许多参与细胞分化的RNA分子相互作用， 以调节细胞中保守的RNA介导的阻遏物复合物。一种ncRNA， 称为TERRA，使LSD 1能够与DNA双链断裂修复相互作用， 在染色体末端（端粒）的酶，证明RNA结合 LSD 1的特性对于基因调控是重要的。TERRA是一种调节RNA， 从酵母转录到人类，可以采用非规范的鸟嘌呤四链体 (GQ)体外和体内的RNA结构。TERRA在细胞中的丰度 随着端粒的逐渐缩短和端粒异染色质的稳定化。 我们假设RNA-LSD 1组装在基因表达中起关键作用， GQ RNA是染色质相关蛋白的重要调节因子。 拟议的研究将1）阐明生物化学和结构机制， TERRA RNA-LSD 1相互作用和2）研究非典型结构RNA如何 接触LSD 1以影响端粒调节途径。长期目标是 该项目旨在了解RNA结构如何影响LSD 1调控网络。 这些研究的结果将为深入了解基于RNA的 表观遗传调控，并作为一个起点，在发展“定制” 以通路特异性方式靶向组蛋白甲基化调节剂的探针。

This research project is centered on the hypothesis that ribonucleic acid (RNA) structure and RNA-chromatin associated protein interactions play crucial roles in maintaining genome stability. Non-coding RNAs (ncRNAs) serve as key regulators of gene expression and are known to physically associate with chromatin-associated proteins to organize changes in gene architecture during specific development stages of the cell. A subset of these RNA-protein interactions are linked to ageing, cancer metastasis, and neuronal development. As genomic approaches begin to identify RNA-protein associations and their links to cancer, there remains limited information about epigenetic-based RNA binding proteins at the molecular level. We seek to understand how RNA functionally interacts with the lysine specific demethylase-1 (LSD1) protein enzyme. LSD1 is an essential histone methylation regulator and has oncogenic properties in several cancers including: prostate, bladder, neuroblastoma, lung, and breast cancer. LSD1 is implicated in cancer through its vast interaction network. LSD1 also interacts with many RNA molecules involved in cell differentiation and can function to regulate conserved RNA-mediated repressor complexes in the cell. An ncRNA, termed TERRA, enables LSD1 to interact with a DNA double strand break repair enzyme at the ends of chromosomes (telomeres), demonstrating that the RNA binding properties of LSD1 are important for gene regulation. TERRA is a regulatory RNA that is transcribed from yeast to humans and can adopt a non-canonical guanine quadruplex (GQ) RNA architecture in vitro and in vivo. TERRA’s abundance in the cell correlates with progressive telomere shortening and the stabilization of telomeric heterochromatin. We hypothesize that RNA-LSD1 assemblies play key roles in gene expression and propose that GQ RNAs serve as crucial regulators of chromatin-associated proteins. The proposed studies will 1) elucidate the biochemical and structural mechanisms of a TERRA RNA-LSD1 interaction and 2) examine how non-canonical structured RNAs contact LSD1 to influence telomeric regulatory pathways. The long-term goal of this project is to understand how RNA structure influences LSD1 regulatory networks. Results from these studies will provide insight into the mechanisms of RNA-based epigenetic regulation and serves as a starting point in the development of ‘tailored’ probes that target histone methylation regulators in a pathway-specific manner.