Developmental regulation of oscillatory expression

振荡表达的发育调节

基本信息

批准号：
10299003
负责人：
Sharon L Amacher
金额：
$ 32.93万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299003
关键词：
3&apos Untranslated Regions Arabidopsis Binding Bioinformatics Biological Pacemakers Biological Process Candidate Disease Gene Cells Cellular biology Clustered Regularly Interspaced Short Palindromic Repeats Development Elements Embryo Embryonic Development Ensure Environment Feedback Fibroblast Growth Factor Gamma Rays Gene Expression Gene Family Genes Genetic Genetic Transcription Hour Human Impairment In Situ Hybridization In Vitro Knock-out Lateral Length Mediating Mesoderm Mesoderm Cell Metabolic Modeling Molecular Molting Mus Mutate Nuclear Pathway interactions Pattern Periodicity Plant Roots Play Poly(A) Tail Post-Transcriptional Regulation Process Proteins RNA Binding Regulation Regulatory Element Reporter Resolution Ribosomes Role Segmentation Clock Pathway Signal Transduction Somites Starvation Stem cell pluripotency System TP53 gene Time Tissue Engineering Tissues Trans-Activators Transcript Transcription Repressor Transgenic Organisms Translating Translational Repression Translations Vertebrates Work Yeasts Zebrafish base biological systems cancer cell cytokine embryonic stem cell experimental study knock-down mutant nerve stem cell notch protein polysome profiling response somitogenesis stem cell biology stem cells transcription factor transcriptome

项目摘要

Project Summary Ultradian oscillatory circuits are pervasive in biological systems. These dynamic oscillators range from pulsatile p53 expression after g-radiation, to periodic nuclear to cytoplasmic shuttling of NFkB transcription factor in response to cytokine, to cyclic expression of Hes/Her transcription factors in stem cells and presomitic mesoderm (PSM). Ultradian genetic oscillators are associated with patterning and developmental transitions – oscillations correlate with yeast metabolic cycles, foreshadow periodic lateral root branching in Arabidopsis, regulate molt cycles in larval worms, associate with stem cell pluripotency, and synchronize transcriptional response to starvation signals in Dictostelium. One biological oscillator is the vertebrate segmentation clock, which controls somitogenesis, the process by which the PSM is sequentially divided into segments called somites. At the core of the segmentation clock is an auto-inhibitory negative feedback loop involving Her/Hes transcriptional repressors, which in turn regulates oscillatory expression of additional ‘cyclic genes’. Although the cyclic genes in human and mouse belong to similar pathways (e.g., Notch, Wnt, FGF, Yap/Hippo), genes in those pathways which are cyclically expressed vary among species, with the Her/Hes gene family genes being common among vertebrates. We study the zebrafish segmentation clock, which oscillates with a 30-minute periodicity and is 4-12 times faster than in mouse or human. In order for a rapid auto-inhibitory oscillator to operate, there must be tight control over synthesis and decay of cyclic gene transcript and protein. A recent experiment in which the Hes7 locus was swapped between human and mouse in vitro PSM systems showed that expression delays and decay, controlled by factors in the host cell environment, are critical regulatory parameters of the clock. To understand the mechanisms regulating these critical parameters, we are using the zebrafish pnrc2 mutant in which transcriptional oscillations occur normally, but post-transcriptional decay mechanisms are disrupted, to identify additional cyclic genes and dissect their regulation. The specific aims of the proposal are to (1) identify Pnrc2-regulated zebrafish embryonic cyclic genes that play critical developmental roles, (2) characterize the regulatory features and factors that control rapid decay dynamics of cyclic gene transcripts, and (3) investigate the role of other post-transcriptional mechanism in regulating segmentation clock function. We anticipate that our work will broadly impact understanding of post- transcriptional mechanisms regulating oscillatory expression in many developmental contexts.

项目概要超电振荡电路在生物系统中普遍存在，这些动态振荡器的范围包括脉动。 g辐射后p53的表达，影响NFkB转录因子的周期性核到细胞质穿梭对细胞因子的反应，对干细胞和成体前细胞中 Hes/Her 转录因子的循环表达的反应中胚层 (PSM) 与模式和发育转变有关 – 振荡与酵母代谢周期相关，预示着拟南芥的周期性侧根分支，调节幼虫的蜕皮周期，与干细胞多能性相关，并使转录同步网柄菌对饥饿信号的反应之一是脊椎动物分节时钟。它控制体细胞发生，PSM 被顺序分成称为节段的过程体节的核心是涉及她/他的自动抑制负反馈循环。转录抑制因子，反过来又调节其他“循环基因”的振荡表达。人类和小鼠的循环基因属于相似的途径（例如，Notch、Wnt、FGF、Yap/Hippo），这些循环表达的途径因物种而异，Her/Hes 基因家族基因是我们研究了斑马鱼的分节时钟，它以 30 分钟为一个周期振荡。周期性，并且比小鼠或人类快 4-12 倍，以便快速自动抑制振荡器。操作时，必须严格控制循环基因转录物和蛋白质的合成和衰变。在体外 PSM 系统中人和小鼠之间交换 Hes7 基因座的实验表明由宿主细胞环境中的因素控制的表达延迟和衰减是关键的调节为了了解调节这些关键参数的机制，我们使用斑马鱼 pnrc2 突变体，其中转录振荡正常发生，但转录后衰退机制被破坏，以识别额外的循环基因并剖析其调控的具体目标。该提案是（1）确定 Pnrc2 调节的斑马鱼胚胎循环基因，这些基因发挥着关键作用发育作用，（2）表征控制快速衰减动态的调节特征和因素循环基因转录本，以及（3）研究其他转录后机制在调节中的作用我们预计我们的工作将广泛影响对后分段时钟功能的理解。在许多发育环境中调节振荡表达的转录机制。