Transcriptome-scale, condition-specific regulation of mRNA isoform stability via the 3'UTR

通过 3UTR 对 mRNA 同工型稳定性进行转录组规模、条件特异性调节

• 批准号: 10230809
• 负责人: Zlata Gvozdenov
• 金额: $ 6.64万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230809
• 关键词: 3' Untranslated Regions; Address; Attention; Binding; Binding Proteins; Bioinformatics; Biological; Catalogs; Cell physiology; Cells; Cleaved cell; Data; Degradation Pathway; Development; Disease; Elements; Equilibrium; Foundations; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Techniques; Genetic Transcription; Genomics; Goals; Growth; Half-Life; Human Biology; Individual; Knowledge; Laboratories; Laboratory Study; Learning; Link; Longevity; Measures; Mediating; Messenger RNA; Methods; Modification; Molecular; Molecular Genetics; Mutation; Nuclear; Nucleotides; Pathway interactions; Physiological; Play; Poly A; Poly(A) Tail; Poly(A)-Binding Protein I; Polyadenylation; Principal Investigator; Process; Property; Protein Isoforms; Proteins; RNA; RNA Decay; RNA Degradation; RNA Polymerase II; RNA-Binding Proteins; Regulation; Research; Research Personnel; Role; Signal Transduction; Site; Structure; System; Techniques; Testing; Training; Transcript; Work; Yeasts; exosome; experience; experimental study; genome-wide; genome-wide analysis; human disease; improved; in vivo; interest; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mutant; operation; proteostasis; response; transcription termination; transcriptome; tumorigenesis

Project Summary/Abstract Altering environmental conditions leads to reprograming of eukaryotic gene expression. One important cellular process that helps adapt gene expression levels to environmental triggers is the regulation of mRNA stability. mRNAs are degraded by specialized cellular machineries, which have been studied in great detail. However, little data exists to explain what cellular signals determine mRNA longevity in response to changing conditions. Alternative polyadenylation allows an individual gene to give rise to multiple distinct mRNA 3’ isoforms. Distinct 3’ isoforms from the same gene can have different half-lives, and the steady-state distribution of mRNA 3’ isoforms can vary under different growth conditions. It is plausible that a diverse array of isoforms is needed for cells to respond to environmental conditions. In part, different isoforms could allow for prompt modulation of gene expression via regulation of mRNA stability. Until now, there have been no genome-wide studies addressing the importance of different isoform profiles for mRNA stabilities under different conditions. This work will comprehensively examine condition-specific isoforms, isoform properties, and cellular factors involved in the regulation of isoform half-lives. In particular, a catalog of isoform half-lives for different growth conditions will be obtained using techniques optimized and/or developed in the Struhl laboratory for studying 3’ isoforms. The isoforms will be subsequently examined for sequence and structural elements. The relevance of any cis-features identified will be directly tested in the context of defective trans-factors, such as degradation machinery components or putative RNA-binding proteins. The proposed work will advance our understanding of the molecular mechanisms that underlie regulated mRNA decay by investigating isoform half-lives and sequence/structural elements under various conditions on a genome-wide scale. The work is expected to reveal 3’ isoform-dependent regulation of mRNA stability by the major degradation pathways and/or RNA-binding proteins in response to environmental triggers. Building on the investigator’s background in nuclear proteostasis, training and expertise in genomics and bioinformatics will be gained. The project will be conducted in a world-renowned transcription group with deep experience in this field, providing a strong foundation for the applicant’s future independent research as a principal investigator in the field of gene expression.

项目摘要/摘要 环境条件的改变导致真核基因表达的重新编程。一个重要的问题 帮助基因表达水平适应环境触发因素的细胞过程是对mRNA的调节 稳定性。MRNAs是通过专门的细胞机制降解的，这些机制已经得到了非常详细的研究。 然而，几乎没有数据来解释是什么细胞信号决定了信使核糖核酸对变化的反应寿命。 条件。交替的多聚腺苷酸化允许单个基因产生多个不同的mRNA3‘ 异构体。来自同一基因的不同3‘亚型可以有不同的半衰期，并且稳态分布 在不同的生长条件下，mRNA3‘亚型的含量会有所不同。一系列不同的异构体是可能的 细胞对环境条件做出反应所需的物质。在某种程度上，不同的亚型可以提供提示 通过调节信使核糖核酸的稳定性调节基因表达。到目前为止，还没有全基因组的 关于不同条件下不同亚型对信使核糖核酸稳定性的重要性的研究。 这项工作将全面检查特定条件的亚型、亚型属性和细胞因子 参与异构体半衰期的调节。特别是，不同生长阶段的亚型半衰期目录 将使用Struhl实验室为研究3‘’而优化和/或开发的技术来获得条件 异构体。随后将检查亚型的序列和结构元素。的关联性 识别的任何顺式特征都将在有缺陷的反式因子(如退化)的背景下直接进行测试 机械部件或假定的RNA结合蛋白。拟议的工作将增进我们对 通过研究亚型半衰期和亚型半衰期调控信使核糖核酸的分子机制 全基因组范围内各种条件下的序列/结构元件。这项工作预计将揭示 主要降解途径和/或RNA结合对mRNA稳定性的3‘异构体依赖性调节 蛋白质对环境刺激的反应。 以研究人员在核蛋白稳定方面的背景为基础，在基因组学和 将获得生物信息学。该项目将在一个世界知名的转录小组中进行，深度 在该领域的经验，为申请人未来的独立研究提供了坚实的基础 基因表达领域的首席研究员。