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 超日振荡回路在生物系统中普遍存在。这些动态振荡器的范围从脉动的 γ射线照射后p53表达，NFkB转录因子周期性地从核到胞质穿梭， 对细胞因子的反应，对干细胞和前体细胞中Hes/Her转录因子的循环表达的反应 中胚层（PSM）。超日基因振荡器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枝， 调节蠕虫的蜕皮周期，与干细胞多能性相关，并同步转录 对饥饿信号的反应。一种生物振荡器是脊椎动物分段时钟， 它控制着体节发生，通过这个过程，PSM被顺序地分成称为 体节分段时钟的核心是一个涉及Her/Hes的自动抑制负反馈回路 转录抑制因子，这反过来又调节振荡表达的额外的“循环基因”。虽然 人和小鼠中的环状基因属于相似的途径（例如，Notch、Wnt、FGF、雅普/Hippo）， 这些周期性表达的途径在物种之间不同，Her/Hes基因家族基因是 在脊椎动物中很常见。我们研究了斑马鱼的分段时钟，它以30分钟的频率振荡， 周期性，比小鼠或人快4-12倍。为了使快速自动抑制振荡器 因此，在生物体中，必须严格控制环状基因转录物和蛋白质的合成和衰变。最近的一 Hes 7基因座在人和小鼠体外PSM系统之间交换的实验显示， 受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因子， 时钟的参数为了理解调节这些关键参数的机制，我们使用 斑马鱼pnrc 2突变体，其中转录振荡正常发生，但转录后衰退 机制被破坏，以确定额外的循环基因，并剖析其调控。的具体目标 本发明建议是：（1）鉴定Pnrc 2调控的斑马鱼胚胎周期基因，这些基因在胚胎发育中起关键作用 发展的作用，（2）表征的监管特点和因素，控制快速衰减动态的 研究其他转录后机制在调控中的作用 分段时钟功能。我们预计，我们的工作将广泛影响后的理解- 在许多发育环境中调节振荡表达的转录机制。