Circadian dynamics of cytoplasmic mRNA polyadenylation and deadenylation

细胞质 mRNA 多腺苷酸化和去腺苷酸化的昼夜动态

基本信息

批准号：
9026882
负责人：
Carla B. Green
金额：
$ 36.18万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-05 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026882
关键词：
Address Animals Behavior Binding Biochemistry Biological CPE-binding protein Cardiovascular system Cell Nucleus Cell physiology Cells Circadian Rhythms Coupled Cytoplasm Data Diabetes Mellitus Diet Embryo Event Excision Exhibits Generations Genes Genetic Transcription Genetic Translation Health Introns Kinetics Learning Length Liver Major Depressive Disorder Mammals Messenger RNA Metabolic Metabolism Molecular Molecular Profiling Mood Disorders Mus Neurons Obesity Pathway interactions Phase Physiology Play Poly(A) Tail Polyadenylation Polyadenylation Pathway Polynucleotide Adenylyltransferase Polyribosomes Post-Transcriptional Regulation Precursor RNA Process Production Protein Biosynthesis Proteins Proteome RNA RNA Processing RNA-Binding Proteins Regulation Resistance Risk Role Site Synapses Tail Testing Time Translating Translational Regulation Translations cancer type circadian pacemaker decapping enzyme dynamic system exosome flexibility genome-wide insight liver function mRNA Decay mRNA Transcript Degradation nocturnin protein expression protein profiling public health relevance sleep abnormalities spleen exonuclease

项目摘要

DESCRIPTION (provided by applicant): Circadian clocks throughout the body drive rhythmic expression of thousands of genes, resulting in rhythms in biochemistry, physiology and behavior. Disruption of these rhythms in mammals has been shown to result in significant health problems. In addition to causing major deleterious effects on metabolism (including obesity and diabetes), increased risk of some types of cancer and cardiovascular problems, recent evidence has also shown a close tie between circadian clocks and affective disorders, sleep abnormalities and major depression. Although circadian control of transcription has been widely studied, recent data have demonstrated that post- transcriptional control, although much less well understood, is also critical for normal rhythmic protein expression profiles. One type of post transcriptional control is regulation of mRNA poly (A) tail length, which impacts the stability and translational regulation of mRNA. We have identified hundreds of mouse liver mRNAs that exhibit robust circadian rhythms in the length of their poly (A) tails. In many of these cases, the rhythmic tail lengths are the result of rhythmic cytoplasmic polyadenylation and deadenylation rhythms and many components of the cytoplasmic polyadenylation and deadenylation machinery are themselves under circadian control. Furthermore, the rhythmic poly (A) tails is closely correlated with the rhythmic protein expression. Therefore, the circadian clock regulates dynamic polyadenylation status of many mRNAs that can drive rhythmic protein expression independent of the steady-state levels of the message. In this proposal, we will explore the mechanisms that cause poly (A) tail rhythms and how these regulate the resulting protein production. In the first specific aim, we will test the hypothesis that the RNA-binding protein CPEB2 binds to specific mRNA targets and controls their polyadenylation state by coordinating the relative activities of deadenylases and poly (A) polymerases in a time of day-dependent manner. In the second specific aim, will test the hypothesis that the deadenylase Nocturnin is responsible for deadenylation and will determine whether deadenylation by Nocturnin leads to decay of those mRNAs that have tails that are modulated during the night phase. And in the third aim we will determine whether the poly (A) tail lengths are themselves the determining factor in regulating the translation of these mRNAs and will examine how the circadian clock controls rhythmic translation. These are important studies because the post-transcriptional mechanisms that regulate poly (A) tail lengths are critical for the generation of the appropriate rhythmic protein profiles and thus the appropriate rhythmic function of the liver.

描述（由申请人提供）：全身的昼夜节律时钟驱动着数千个基因的节律性表达，导致哺乳动物的生物化学、生理学和行为节律的破坏除了引起严重的健康问题之外。生物钟对新陈代谢（包括肥胖和糖尿病）产生重大有害影响，某些类型的癌症和心血管问题的风险增加，最近的证据还表明，生物钟与情感障碍、睡眠异常和主要疾病之间存在密切联系。尽管转录的昼夜节律控制已被广泛研究，但最近的数据表明，转录后控制虽然还不太了解，但对于正常节律性蛋白质表达谱也至关重要。转录控制是对 mRNA 聚 (A) 尾长度的调节，这会影响稳定性和我们已经鉴定出数百种小鼠肝脏 mRNA，其多聚 (A) 尾的长度表现出强大的昼夜节律。节律性尾长度是节律性细胞质多聚腺苷酸化和去腺苷酸化节律的结果，并且细胞质多聚腺苷酸化和去腺苷酸化机制的许多组成部分本身受到昼夜节律控制。此外，节律性聚腺苷酸尾与节律性蛋白质表达密切相关。生物钟调节许多 mRNA 的动态多聚腺苷酸化状态，这些 mRNA 可以独立于消息的稳态水平驱动有节律的蛋白质表达。探索引起 Poly (A) 尾节律的机制以及这些机制如何调节由此产生的蛋白质生产。在第一个具体目标中，我们将测试 RNA 结合蛋白 CPEB2 与特定 mRNA 靶标结合并通过协调控制其多腺苷酸化状态的假设。去腺苷酸酶和聚腺苷酸聚合酶的相对活性以一天中的时间依赖性方式进行。在第二个具体目标中，将测试去腺苷酸酶 Nocturnin 负责去腺苷酸化的假设，并确定是否会发生去腺苷酸化。 Nocturnin 的去腺苷酸化会导致具有在夜间阶段受到调节的尾部的 mRNA 的衰变，并且在第三个目标中，我们将确定 Poly (A) 尾部长度本身是否是调节这些 mRNA 翻译的决定因素。检查生物钟如何控制节律翻译，这些都是重要的研究，因为调节聚腺苷酸尾长度的转录后机制对于生成适当的节律蛋白质谱以及肝脏的适当节律功能至关重要。