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

项目总结/摘要 改变环境条件导致真核基因表达的重编程。一个重要 一个帮助基因表达水平适应环境触发的细胞过程是mRNA的调节 稳定mRNA被专门的细胞机制降解，这已经被非常详细地研究过。 然而，几乎没有数据可以解释是什么细胞信号决定了mRNA的寿命， 条件选择性多聚腺苷酸化允许单个基因产生多个不同的mRNA 3'端。 同种型。来自相同基因的不同3'亚型可以具有不同的半衰期，并且稳态分布 在不同的生长条件下，mRNA 3'亚型的表达可能不同。似乎有理由认为， 细胞对环境条件的反应所需的。在某种程度上，不同的同种型可以允许快速的 通过调节mRNA稳定性来调节基因表达。到目前为止，还没有全基因组的 研究解决了不同条件下mRNA稳定性的不同异构体谱的重要性。 这项工作将全面检查条件特异性异构体，异构体的性质，和细胞因子 参与同种型半衰期的调节。特别是，不同生长的异构体半衰期的目录 将使用Struhl实验室优化和/或开发的技术获得条件，用于研究3' 同种型。随后将检查亚型的序列和结构元件。的相关性 任何确定的顺式特征将在有缺陷的反式因子的背景下直接测试， 机械组件或推定的RNA结合蛋白。拟议的工作将促进我们对以下问题的理解： 通过研究异构体半衰期， 序列/结构元件在各种条件下在全基因组范围内。这项工作预计将揭示 通过主要降解途径和/或RNA结合对mRNA稳定性的3'亚型依赖性调节 蛋白质对环境触发的反应。 基于研究者在核蛋白质稳态方面的背景，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组进行， 在这一领域的经验，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

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.