Developmental regulation of oscillatory expression

振荡表达的发育调节

• 批准号: 10456210
• 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
• 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/10456210
• 关键词: 3' 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

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.

项目摘要 超级振荡器电路在生物系统中普遍存在。这些动态振荡器范围从脉动 G辐射后的p53表达，以定期核至NFKB转录因子的细胞质穿梭 对细胞因子的反应，对干细胞和Presomitic中HES/她的转录因子的环状表达 中胚层（PSM）。超级遗传振荡器与图案和发育过渡有关 - 振荡与酵母代谢周期相关，预示了拟南芥中周期性的侧根分支， 调节幼虫蠕虫中的蜕皮循环，与干细胞多能相关，并同步转录 对Dictostelium中饥饿信号的响应。一个生物振荡器是脊椎动物分段时钟， 控制体重生成的过程，将PSM顺序分为段的过程称为段 节。分段时钟的核心是涉及她/HES的自动抑制作用反馈回路 转录复制品，反过来调节其他“环状基因”的振荡表达。虽然 人和小鼠中的环状基因属于相似途径（例如Notch，Wnt，FGF，YAP/Hippo），中的基因 在物种之间周期表达的途径有所不同，而HER/HES基因家族基因为 在脊椎动物中常见。我们研究斑马鱼分段时钟，该时钟以30分钟的时间振荡 周期性，比小鼠或人类快4-12倍。为了快速自动抑制振荡器 操作，必须严格控制环状基因转录和蛋白质的合成和衰减。最近 在体外PSM系统中，将HES7基因座交换在HES7基因座的实验中 这种表达延迟和衰减受宿主细胞环境中的因素控制，是关键的调节 时钟的参数。要了解调查这些关键参数的机制，我们正在使用 转录振荡正常发生的斑马鱼PNRC2突变体，但转录后衰减 机制被破坏，以识别其他环状基因并剖析其调节。具体目的 该建议是（1）识别pNRC2调节的斑马鱼胚胎环状基因 发展角色，（2）表征控制快速衰减动力学的调节特征和因素 环状基因转录本，（3）研究其他转录后机制在调节中的作用 分段时钟功能。我们预计我们的工作将广泛影响对邮政的理解 在许多发育环境中恢复振荡表达的转录机制。