Regulation of pre-ribosomal RNA by the Circadian Clock

昼夜节律钟对前核糖体 RNA 的调节

• 批准号: 9788052
• 负责人: Marlene Cervantes
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788052
• 关键词: ARNTL gene; Acetylation; Affect; Biogenesis; Bioinformatics; Biological Clocks; Biological Process; Carrier Proteins; Cell Nucleolus; Circadian Dysregulation; Circadian Rhythms; Clock protein; Complex; DNA Sequence; DNA-Directed RNA Polymerase; Data Set; Development; Diabetes Mellitus; Disease; Event; Feedback; Follow-Up Studies; Genes; Genetic Transcription; Goals; Guide RNA; Histone H3; Hour; Jet Lag Syndrome; Laboratories; Lead; Location; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Mediating; Metabolism; Methylation; Modification; Molecular; Morphology; Nuclear; Nuclear Protein; Nucleolar Proteins; Obesity; Pathology; Pattern; Periodicity; Physiology; Play; Polymerase; Post-Translational Protein Processing; Process; Production; Proteins; Proteome; Proteomics; Publishing; RNA Polymerase I; RNA Processing; RNA, Ribosomal, 28S; Regulation; Reporting; Repressor Proteins; Ribonucleoproteins; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Series; Site; Sleep; Small Nucleolar RNA; Structure; System; Tandem Repeat Sequences; Testing; Time; Transcript; base; circadian; circadian pacemaker; circadian regulation; histone acetyltransferase; interest; molecular scale; novel; novel therapeutics; rRNA Precursor; recruit; research study; shift work; sleep pattern; therapeutic development; transcription factor; transcriptome sequencing

Project Summary Disruptions of the body's internal circadian clock by means such as jet lag, a lack of sleep or shift work can affect biological functions and lead to disease. Becoming more familiar with the regulation of circadian rhythms will allow for a better understanding of pathologies such as obesity, diabetes, and cancer and the development of therapeutic treatments for these diseases. On a molecular scale, the circadian clock controls many cellular mechanisms that give the biological clock the ability to remain at a constant 24-hour period. The core clock machinery, CLOCK and BMAL1, regulates transcription of clock-controlled genes. Additionally, CLOCK has also been found to have a non-traditional role in post-translational modifications such as the acetylation levels of circadian proteins. However, additional roles for BMAL1 are not well identified. Hints provided by recent discoveries indicate the clock is involved RNA polymerase 1 (Pol I)-mediated transcription. Pol I transcribes ribosomal DNA (rDNA) that is further processed to mature ribosomal RNA (rRNA) through a series of post-transcriptional modifications. The rRNA precursor, (pre-rRNA), is a tandem repeat that contains 18S, 5.8S and 28S rRNAs. A study on circadian nuclear protein accumulation has shown an oscillatory expression pattern of nucleolar proteins involved in pre-rRNA processing. Based on the recent findings, the goal of this project is to elucidate the function of the circadian clock on the regulation of pre-rRNA. This study will explore the undiscovered mechanism for the circadian pre-rRNA expression. First, a novel BMAL1 subcellular localization will be identified and fully characterized. Further, the circadian regulation of pre- rRNA will be investigated by preforming analyses to locate the sites of BMAL1 recruitment to rDNA. Measurements of the Pol I transcriptional activity in a clock-dependent manner will define the role of the circadian clock on pre-rRNA transcription. Additionally, this research study will identify a novel role for BMAL1 on pre-rRNA maturation. The importance of a physical interaction between BMAL1 and the nucleolar proteins will be thoroughly established. Followed by a comprehensive analysis of the role of the circadian clock on nucleolar structural integrity. Lastly, we will test the significance of the nucleolar BMAL1 in pre-rRNA processing. We believe we will characterize the functional relevance of BMAL1 in the nucleolus. !

项目摘要 由于时差、睡眠不足或轮班工作等原因，身体内部的生物钟受到干扰， 影响生物功能并导致疾病。更熟悉昼夜节律的调节 将有助于更好地了解肥胖、糖尿病和癌症等疾病， 这些疾病的治疗方法。 在分子尺度上，生物钟控制着许多细胞机制，这些机制赋予生物钟以 保持24小时不变的能力。核心时钟机械CLOCK和BMAL 1调节 生物钟控制基因的转录。此外，还发现时钟具有非传统的作用 在翻译后修饰，如昼夜节律蛋白的乙酰化水平。然而，额外的角色 BMAL 1没有被很好地识别。最近的发现提供的线索表明，生物钟与RNA有关。 聚合酶I（Pol I）介导的转录。Pol I转录核糖体DNA（rDNA）， 通过一系列转录后修饰使核糖体RNA（rRNA）成熟。rRNA前体， 前体rRNA是一种包含18 S、5.8S和28 S rRNA的串联重复序列。昼夜节律核蛋白的研究 积累显示了参与前rRNA的核仁蛋白质的振荡表达模式 处理.基于最近的发现，本项目的目标是阐明昼夜节律的功能 时钟对pre-rRNA的调节。 本研究将探索尚未发现的昼夜前rRNA表达机制。首先，一部小说 将鉴定并充分表征BMAL 1亚细胞定位。此外，昼夜调节的前- 将通过预成形分析研究rRNA，以定位BMAL 1募集至rDNA的位点。 以时钟依赖性方式测量Pol I转录活性将定义转录因子的作用。 生物钟对前rRNA转录的影响。 此外，这项研究将确定BMAL 1在前rRNA成熟中的新作用。的重要性 BMAL 1和核仁蛋白之间的物理相互作用将被彻底建立。其次是 全面分析昼夜节律钟对核仁结构完整性的作用。最后，我们将测试 核仁BMAL 1在pre-rRNA加工中的意义。我们相信我们将描述功能性的 BMAL 1在核仁中的相关性。 !