Multi-layered Control of the Exit from Stemness

Stemness 退出的多层控制

基本信息

批准号：
10334555
负责人：
Cheng-Yu Lee
金额：
$ 33.03万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334555
关键词：
3&apos Untranslated Regions BRAT gene Binding Brain Brain Neoplasms Cell Lineage Cells Complex Cullin Proteins DNA-Binding Proteins Development Drosophila genus Ensure Gene Expression Regulation Genes Genetic Transcription Homologous Gene Inherited Knowledge Lead Mediating Messenger RNA Oranges Outcome Pattern Post-Transcriptional Regulation Protein Family Proteins Proteolysis RNA-Binding Proteins Regulation Role Series Signal Transduction Structure System Testing Time Transcript Transcriptional Regulation Translations Tumor Burden Tumor Stem Cells base cell fate specification cell type defined contribution dimer experimental study fly gene function improved in vivo Model insight mRNA Decay monomer multimodality nerve stem cell neuroblast neurogenesis notch protein novel strategies progenitor protein complex recruit self-renewal spatiotemporal stem cells stemness ubiquitin-protein ligase

项目摘要

The mechanisms promoting the exit from stemness in normal neural stem cells likely can also drive brain tumor stem cells to differentiate. Thus, insights into control of the exit from stemness will improve our understanding of normal neurogenesis as well as brain tumor development. To exit from stemness, neural stem cell progeny must synchronously terminate self-renewal gene activity at the level of mRNAs and proteins. While tremandous progress has been made toward understanding the termination of self-renewal gene transcription during the exit from stemness, little is known about how post-transcriptional regulatory mechanisms terminate self-renewal gene activity. Importantly, nothing is known about how distinct control layers function synergistically to terminate self-renewal gene activity at all levels. By using the fly type II neural stem cell lineage as a paradigm, we demonstrated that transcriptional, translational and post-translational control function as part of an integrated gene regulation system that synchronously terminates self-renewal gene activity at all levels in the stem cell progeny. In this proposal, we focus on translational and post- translational control of self-renewal gene activity. We showed that RNA-binding protein complexes that are active in the stem cell progeny expedite self-renewal gene transcripts for decay by binding unique sequences in their 3'UTRs and recruiting multiple deadenylase concurrently. In addition, we showed that the combined effect of protein sequestration and proteolysis directed by multiple ubiquitin E3 ligase complexes rapidly and robustly terminates self-renewal protein activity. A robust transition from an “ON” to an “OFF” state is also required for precise spatiotemporal activity of many developmental signaling mechanisms that control patterning, proliferation and cell fate specification. Insights into our proposed integrated gene regulation system will be broadly applicable to the control of the exit from stemness in all stem cell lineages as well as the regulation of numerous cell fate decisions during normal development.

促进正常神经干细胞退出干性的机制可能也可以驱动大脑因此，对干性退出控制的深入了解将改善我们的研究。了解正常的神经发生以及脑肿瘤的发展摆脱干性，神经。干细胞后代必须在 mRNA 和蛋白质水平上同步终止自我更新基因活性。虽然在理解自我更新基因的终止方面已经取得了巨大进展干性退出期间的转录，但对于转录后调控如何进行知之甚少重要的是，我们对如何不同的控制机制一无所知。通过使用果蝇 II 型神经，各层协同发挥作用，终止各个级别的自我更新基因活动。干细胞谱系作为范例，我们证明了转录、翻译和翻译后控制功能作为同步终止自我更新的整合基因调控系统的一部分干细胞后代各个水平的基因活性在本提案中，我们重点关注翻译和后处理。我们发现RNA结合蛋白复合物是自我更新基因活性的翻译控制。在干细胞后代中活跃，通过结合独特的序列加速自我更新基因转录本的衰变此外，我们还发现，在它们的 3'UTR 中同时招募多个去腺苷酸酶。由多个泛素 E3 连接酶复合物快速和快速地指导蛋白质隔离和蛋白水解作用稳健地终止自我更新蛋白质活性也是从“ON”到“OFF”状态的稳健转变。控制许多发育信号机制的精确时空活动所需深入了解我们提出的整合基因调控系统。将广泛适用于控制所有干细胞谱系的干性退出以及正常发育过程中许多细胞命运决定的调节。