Mechanisms of RNA turnover during the epithelial-mesenchymal transition

上皮-间质转化过程中 RNA 周转的机制

• 批准号: 10714965
• 负责人: Erica Hutchins
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714965
• 关键词: Automobile Driving; Biological Models; Biological Process; Biology; Candidate Disease Gene; Cells; Development; Disease; Epithelium; Fibrosis; Gene Expression; Genetic Transcription; Health; Human; Hybrids; Malignant Neoplasms; Mesenchymal; Natural regeneration; Neural Crest; Neural Crest Cell; Pathologic; Post-Transcriptional Regulation; Process; RNA; RNA-Binding Proteins; Residual state; Role; Testing; Transcript; Transcriptional Activation; multiple omics; novel; programs; transcriptome sequencing; wound healing

Project Summary/Abstract Cells alter their gene expression landscape to change their cellular state. The ability of cells to quickly transit between cell states is essential for many processes in biology—from development to wound healing and regeneration, processes which often go awry in pathological conditions like cancer or fibrosis. Thus, there is a biomedical need to understand the basic mechanisms driving these rapid cellular transitions. The epithelial- mesenchymal transition (EMT) is one such cellular transition that has reiterative roles in human health and disease. While much is known about the transcriptional programs that promote EMT, there are additional levels of gene expression control that impact cell state transitions and by extension EMT. The role of post- transcriptional regulation, and how it drives and contributes to a spectrum of EMT states, is not well understood. Here, we examine the role of post-transcriptional regulation, with emphasis on transcript turnover, during EMT. Neural crest cells undergo a tightly regulated EMT and offer a tractable model system in which to investigate the basic mechanisms of RNA turnover during EMT. We hypothesize that, in addition to pro-EMT transcriptional activation, transcripts that inhibit EMT (anti- EMT) or serve to maintain a previous cellular state must be degraded to drive EMT and cell state transitions. Using neural crest EMT as a model system, we seek to test this hypothesis by answering the following questions: 1) How are anti-EMT and residual transcripts targeted for turnover; and 2) What are the targets of RNA turnover during EMT and how does specific RNA turnover contribute to hybrid EMT states? To answer these questions, we will: 1) Apply a combination of unbiased multi-omic and candidate gene approaches to identify the RNA-binding proteins that promote RNA turnover during EMT; and 2) Apply RNA-sequencing approaches to broadly identify the targets of RNA turnover, the mechanism of how they are turned over, and how this contributes to hybrid EMT states. This Proposal seeks to understand the mechanisms of RNA turnover during EMT. The results of these studies will greatly advance current understanding of the basic cellular mechanisms driving EMT, providing novel targets for modulating EMT in human health and disease.

项目概要/摘要 细胞改变其基因表达景观以改变其细胞状态。细胞快速反应的能力 细胞状态之间的转换对于生物学的许多过程至关重要——从发育到伤口愈合和 再生，在癌症或纤维化等病理条件下经常出错的过程。因此，有一个 生物医学需要了解驱动这些快速细胞转变的基本机制。上皮- 间充质转化（EMT）就是这样一种细胞转化，它在人类健康和免疫系统中具有反复的作用。 疾病。虽然人们对促进 EMT 的转录程序了解很多，但还有其他水平 影响细胞状态转变和延伸的 EMT 的基因表达控制。后的作用 转录调控，以及它如何驱动和促进一系列 EMT 状态，目前尚不清楚 明白了。在这里，我们研究转录后调控的作用，重点是转录本周转， 急救期间。神经嵴细胞经历严格调控的 EMT，并提供一个易于处理的模型系统，在该系统中 研究 EMT 过程中 RNA 周转的基本机制。 我们假设，除了促 EMT 转录激活之外，抑制 EMT 的转录物（抗 EMT） EMT）或用于维持先前细胞状态的功能必须被降解以驱动 EMT 和细胞状态转变。 使用神经嵴 EMT 作为模型系统，我们试图通过回答以下问题来检验这一假设 问题：1）抗EMT和残留成绩单如何针对周转； 2）目标是什么 EMT 期间的 RNA 周转以及特定 RNA 周转如何影响混合 EMT 状态？来回答 针对这些问题，我们将：1）应用无偏见的多组学和候选基因方法的组合来 鉴定在 EMT 过程中促进 RNA 周转的 RNA 结合蛋白； 2) 应用 RNA 测序 广泛识别 RNA 周转目标的方法、它们如何周转的机制，以及 这对混合应急医疗队状态有何贡献。 本提案旨在了解 EMT 期间 RNA 周转的机制。这些结果 研究将极大地推进目前对驱动 EMT 的基本细胞机制的理解，提供 调节人类健康和疾病中的 EMT 的新靶标。