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

阐明非编码 RNA - LSD1 相互作用的结构和功能

• 批准号: 9260218
• 负责人: Nicholas J Reiter
• 金额: $ 13.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2017-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260218
• 关键词: Adopted; Aging; Architecture; Binding; Binding Proteins; Biochemical; Biological Assay; Biological Models; Biology; Bladder; Cell Differentiation process; Cell physiology; Cells; Chromatin; Chromosomal Stability; Chromosomes; Circular Dichroism; Complex; DNA Damage; DNA Double Strand Break; Degenerative Disorder; Development; Disease; Electrophoretic Mobility Shift Assay; Elements; Enzymes; Epigenetic Process; Excision; Future; G-Quartets; Gap Junctions; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome Stability; Genomic approach; Goals; Guanine; Heterochromatin; Histones; Human; Human Genome; Hybrids; Immunofluorescence Immunologic; Immunoprecipitation; In Vitro; KDM1A gene; Kinetics; Lead; Length; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Molecular; Mono-S; Multienzyme Complexes; Mutation Analysis; Neoplasm Metastasis; Neuroblastoma; Nucleic Acid Binding; Oncogenic; Pathway interactions; Play; Positioning Attribute; Property; Prostate; Proteins; RNA; Recruitment Activity; Regulator Genes; Regulatory Pathway; Research Project Grants; Resolution; Ribonucleosides; Role; Signal Transduction; Specificity; Structure; Telomere Shortening; Tertiary Protein Structure; Transcriptional Regulation; Untranslated RNA; X-Ray Crystallography; Yeasts; analytical ultracentrifugation; base; chromatin remodeling; crosslink; demethylation; epigenetic regulation; functional group; histone methylation; human disease; in vivo; insight; malignant breast neoplasm; neuron development; nucleic acid structure; programs; protein complex; protein function; repair enzyme; response; scaffold; structural biology; telomere; therapeutic development; therapeutic target; transcription factor

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.

本研究项目围绕核糖核酸（RNA）结构假说展开