Uncovering the Gene Regulatory Mechanisms Governing the Aging Circadian Clock

揭示控制衰老生物钟的基因调控机制

基本信息

批准号：
9565022
负责人：
David Anthony Hendrix
金额：
$ 35.99万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565022
关键词：
Address Affect Age Aging Animal Model Autopsy Binding Binding Sites Biological Biological Assay Biology of Aging Brain Cell physiology Cessation of life ChIP-seq Chromatin Chronobiology Circadian Rhythms Collection Complex Computational Biology DNA Binding DNA Polymerase II Data Dimerization Disease Drosophila genus Elderly Erythroid Event Exhibits Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Global Change Head Health Heat shock factor Homeostasis Human Hypoxia Hypoxia Inducible Factor Immunoprecipitation Individual Knowledge Lead Learning Life Life Cycle Stages Longevity Mass Spectrum Analysis Measures Mediating MicroRNAs Modification Molecular Mus Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Neurophysiology - biologic function Nuclear Orthologous Gene Oxidative Stress Pathology Pathway interactions Pattern Periodicity Phenocopy Physiological Processes Play Post-Transcriptional Regulation Predisposition Promoter Regions RNA Polymerase II Regulation Regulator Genes Regulatory Element Role Site Small RNA Stress System Testing Time Transcriptional Regulation Transposase Work age effect age related base biological adaptation to stress chromatin modification chromatin remodeling circadian pacemaker coping mechanism dimer fly genome-wide healthy aging hypoxia inducible factor 1 insight novel oxidative damage promoter response transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY: Circadian clocks are important regulators of cellular functions and homeostasis. Age- related alterations in the human circadian system are implicated in neuronal pathologies. Recent evidence in fruit flies and mice suggests correlation between disrupted rhythms and neurodegeneration; however, very little is known about mechanisms involved. To address these mechanisms, we compared circadian transcriptome in heads of young and old Drosophila using RNA-seq. We found that several genes that were expressed in young flies in a rhythmic fashion lose cycling pattern to become constitutively low or high in old flies. We uncovered a group of genes, which were low and arrhythmic in heads of young flies but became strongly rhythmic in heads of old flies. This group contains known stress-responsive genes that are induced in young flies in response to oxidative stress or hypoxia. Based on our preliminary data, we hypothesize that clock orchestrates rhythmic expression of neuroprotective genes, which we termed late life cyclers (LLCs), in response to intrinsic stress and damage in the aging nervous system. In Aim 1, we will measure genome-wide binding of the core circadian transcription factors CLK and CYC through ChIP-Seq and identify age-specific binding events that could be responsible for these regulatory changes. In Aim 2, we will measure chromatin modifications H3K4me3 and H3K27me3 as well as RNA Polymerase II binding using ChIP-Seq around the clock in young and old fly heads to characterize the effect of age-altered chromatin state and transcriptional changes associated with aging. In Aim 3, we will measure microRNA expression around the clock in young and old flies, to identify age-altered microRNA regulatory events that could result in post-transcriptional changes in rhythmic gene expression. The proposed work should reveal clock-controlled pathways that protect brain from age-related damage. Given the conserved molecular basis of circadian clock and aging biology, we expect these pathways will also function in humans. !

项目摘要：昼夜节律时钟是细胞功能和稳态的重要调节因子。年龄- 人类昼夜节律系统的相关变化与神经元病理有关。果蝇和小鼠的最新证据表明，有节奏和神经变性；但是，关于涉及的机制知之甚少。解决这些机制，我们使用了使用果蝇的年轻人和老年果蝇头部的昼夜节律转录组 RNA-seq。我们发现以节奏方式以年轻苍蝇表达的几个基因失去骑自行车的模式，使旧蝇的组成性低或高。我们发现了一群基因，年轻苍蝇的头部低且心律不齐，但在旧苍蝇的头。该组包含已诱导的已知应力响应基因年轻的苍蝇响应氧化应激或缺氧。根据我们的初步数据，我们假设时钟策划了神经保护基因的节奏表达，我们被称为后期自行车运动员（LLC），响应内在的压力和衰老神经的损害系统。在AIM 1中，我们将测量核心昼夜节律转录的全基因组结合因素通过CHIP-seq和CYC进行CHIP-seq，并确定可能是年龄特异性的结合事件负责这些监管变化。在AIM 2中，我们将测量染色质修饰 H3K4ME3和H3K27ME3以及RNA聚合酶II结合，使用芯片seq围绕年轻人和老蝇头的时钟，以表征改变年龄的染色质状态和转录变化与衰老有关。在AIM 3中，我们将测量microRNA表达在年轻人和老蝇中全天候，以确定改变年龄的microRNA调节事件可能导致节奏基因表达的转录后变化。拟议的工作应揭示可保护大脑免受年龄相关损害的时钟控制途径。鉴于昼夜节律和衰老生物学的保守分子基础，我们希望这些途径将还在人类中发挥作用。呢