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DEFINING THE ROLE OF RNA SEQUESTRATION IN MAMMALIAN CELL FATE

定义 RNA 隔离在哺乳动物细胞命运中的作用

基本信息

批准号：
10686100
负责人：
Bruno Di Stefano
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-18 至 2027-06-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY Cell fate transitions prompt widespread changes in gene expression programs that require multiple levels of regulation to specify and ultimately restrict cell identity. Post-transcriptional mechanisms are fundamental regulators of gene expression and have recently emerged as critical to establishing and maintaining cell identity. However, the role of post-transcriptional mechanisms in development and tissue homeostasis remains poorly understood. The long-term goal of my research program is to define the role of post-transcriptional regulation in mammalian cell fate decisions in order to develop new therapeutic strategies for regenerative medicine and cancer. The objective of this proposal is to characterize the function of post-transcriptional mechanisms in embryogenesis and adult tissue homeostasis. Our central hypothesis is that the sequestration of RNAs in cytoplasmic condensates has crucial roles during developmental transitions and is important to maintain cellular identity and tissue homeostasis. Although cytoplasmic RNA condensates are thought to play important roles in various RNA-related processes, their molecular function and role in mammalian cell fate transitions are poorly understood. In the first Project, we will elucidate how RNA sequestration instructs embryonic cell fate transitions. We will track early lineage decisions following perturbation of RNA sequestration in early embryos. Moreover, we will define the first landscape of RNA condensates in embryonic stem cells as well as endoderm, ectoderm, and mesoderm progenitors. We then will assess how transcript isoforms and RNA methylation influence compartment-specific regulation of RNAs in pluripotent stem cells. In the second Project, we will determine the role of post-transcriptional mechanisms during tissue homeostasis. Specifically, we will explore the cellular, molecular, and functional role of RNA sequestration in hematopoiesis. Further, we will utilize several innovative tools and cutting-edge technologies, including profiling of the RNA content of cytoplasmic condensates and translatome mapping in hematopoietic stem cells, to dissect the mechanisms by which RNA sequestration controls hematopoietic cell identity. Collectively, this work will reveal how RNA processing drives key aspects of lineage-specific mammalian cell fate trajectories. Uncovering and understanding novel regulatory mechanisms that control cell fate decisions is a crucial step to develop approaches for regenerative medicine and cancer. We, therefore, anticipate that the proposed work will have important implications for both basic science and translational medicine.

项目摘要细胞命运转变促使基因表达程序发生广泛变化，这些程序需要多个水平的基因表达调控。监管规定并最终限制小区身份。转录后机制是基础基因表达的调节因子，最近发现对于建立和维持细胞身份至关重要。然而，转录后机制在发育和组织稳态中的作用仍然很差明白我的研究计划的长期目标是确定转录后调节在哺乳动物细胞命运的决定，以开发新的治疗策略，再生医学和癌本提案的目的是描述转录后机制在胚胎发生和成体组织稳态。我们的中心假设是，RNA的隔离在细胞质凝聚物在发育转变过程中起着至关重要的作用，身份和组织内稳态。虽然细胞质RNA浓缩物被认为在细胞内的转录中起重要作用，各种RNA相关的过程，它们的分子功能和在哺乳动物细胞命运转变中的作用很差，明白在第一个项目中，我们将阐明RNA螯合如何指导胚胎细胞的命运转变。我们将跟踪早期胚胎中RNA螯合扰动后的早期谱系决定。此外，委员会认为，我们将定义胚胎干细胞以及内胚层，外胚层，和中胚层祖细胞。然后，我们将评估转录异构体和RNA甲基化如何影响多能干细胞中RNA的隔室特异性调节。在第二个项目中，我们将确定转录后机制在组织稳态中的作用。具体来说，我们将探索细胞， RNA螯合在造血中的分子和功能作用。此外，我们将利用一些创新的工具和尖端技术，包括分析细胞质浓缩物的RNA含量，造血干细胞中的翻译组图谱，以剖析RNA封存的机制控制造血细胞的特性。总的来说，这项工作将揭示RNA加工是如何驱动谱系特异性哺乳动物细胞命运轨迹。发现和理解新的调控机制控制细胞命运的决定是开发再生医学和癌症方法的关键一步。因此，我们预计，拟议中的工作将对基础科学和转化医学