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. !

项目概要 时差、睡眠不足或轮班工作等都会扰乱人体的内部生物钟 影响生物功能并导致疾病。更加熟悉昼夜节律的调节 将有助于更好地了解肥胖、糖尿病和癌症等病理学及其发展 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，使生物钟 保持24小时恒定的能力。核心时钟机制 CLOCK 和 BMAL1 负责调节 时钟控制基因的转录。此外，CLOCK还被发现具有非传统作用 翻译后修饰，例如昼夜节律蛋白的乙酰化水平。然而，额外的角色 BMAL1 尚未得到很好的鉴定。最近的发现提供的线索表明时钟与RNA有关 聚合酶 1 (Pol I) 介导的转录。 Pol I 转录核糖体 DNA (rDNA)，并进行进一步处理 通过一系列转录后修饰，使核糖体RNA (rRNA) 成熟。 rRNA前体， (pre-rRNA) 是包含 18S、5.8S 和 28S rRNA 的串联重复序列。昼夜节律核蛋白的研究 积累显示出参与前 rRNA 的核仁蛋白的振荡表达模式 加工。根据最近的发现，该项目的目标是阐明昼夜节律的功能 时钟对前 rRNA 的调节。 本研究将探索昼夜节律前 rRNA 表达的尚未发现的机制。首先是小说 BMAL1 亚细胞定位将被识别并充分表征。此外，昼夜节律调节 将通过进行分析来研究 rRNA，以定位 BMAL1 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 Pol I 转录活性的作用 rRNA 前体转录的生物钟。 此外，这项研究将确定 BMAL1 在 rRNA 前体成熟中的新作用。重要性 BMAL1 和核仁蛋白之间的物理相互作用将得到彻底确立。其次是 全面分析生物钟对核仁结构完整性的作用。最后我们来测试一下 核仁 BMAL1 在前 rRNA 加工中的重要性。我们相信我们将表征功能 BMAL1 在核仁中的相关性。 ！