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.

项目摘要/摘要 细胞改变其基因表达景观以改变其细胞状态。细胞快速的能力 细胞状态之间的过境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，通常在癌症或纤维化等病理状况下出现问题的过程。那有一个 生物医学需要了解驱动这些快速细胞过渡的基本机制。上皮 间充质转变（EMT）是一种在人类健康中具有重复性作用的细胞过渡和 疾病。虽然对促进EMT的转录程序知之甚少，但还有其他级别 基因表达控制会影响细胞状态转变和扩展EMT。后的作用 转录调节及其如何驱动和促进EMT状态的驱动和贡献不佳 理解齿。在这里，我们研究了转录后调节的作用，重点是转录本的周转， 在EMT期间。神经rest细胞经历严格调节的EMT，并提供可拖动的模型系统 研究EMT期间RNA转换的基本机制。 我们假设，除了促进EMT转录激活外，抑制EMT的转录本（抗抗液） EMT）或用于维持先前的细胞状态必须降解以驱动EMT和细胞状态过渡。 使用Neural Crest EMT作为模型系统，我们试图通过回答以下内容来检验这一假设 问题：1）如何针对营业额的反EMT和残留转录本； 2）目标是什么 EMT期间的RNA转换以及特定的RNA更新如何促进混合EMT状态？回答 这些问题，我们将：1）将无偏的多摩变和候选基因方法的组合用于 确定在EMT期间促进RNA转换的RNA结合蛋白； 2）应用RNA序列 广泛识别RNA转换目标的方法，其如何翻转的机制以及 这如何促进混合EMT国家。 该提案旨在了解EMT期间RNA转换的机制。这些结果 研究将大大提高人们对驱动EMT的基本蜂窝机制的理解，从而提供 调节EMT在人类健康和疾病中的新目标。