无处不在的 GC 含量特征是 DDX3X 多模式 mRNA 调控的基础。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-03-01 Epub Date: 2024-01-25 DOI:10.1038/s44320-024-00013-0
Ziad Jowhar, Albert Xu, Srivats Venkataramanan, Francesco Dossena, Mariah L Hoye, Debra L Silver, Stephen N Floor, Lorenzo Calviello
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引用次数: 0

摘要

从转录到蛋白质合成的过程障碍重重,因此转录后基因表达调控有多种模式。DDX3X 是 mRNA 生物学中的一个基本角色,它是一种 RNA 结合蛋白,能规范地调节 mRNA 翻译。通过监测 DDX3X 缺失后 mRNA 丰度和翻译的动态,我们观察到翻译受抑制的 mRNA 趋于稳定。我们利用可解释的统计学习模型发现,编码序列中的 GC 含量是 RNA 稳定的主要特征。这一结果证实了其他研究中检测到的与 GC 含量相关的 mRNA 调控,包括数百个 ENCODE 数据集和最近关注细胞周期中 mRNA 动态的研究。我们通过详细分析数百个样本(包括表现出细胞周期和神经发生缺陷的 Ddx3x 条件性基因敲除小鼠模型)的 RNA-seq 图谱,进一步证明了 mRNA 的稳定性。我们的研究确定了 mRNA 调控的一个普遍特征,并强调了量化基因表达级联多个步骤的重要性,因为 RNA 丰度和蛋白质的产生往往是不耦合的。
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A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X.

The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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