Transcriptome-wide stability analysis uncovers LARP4-mediated NFκB1 mRNA stabilization during T cell activation
Transcriptome-wide stability analysis uncovers LARP4-mediated NFκB1 mRNA stabilization during T cell activation
复制标题
全转录组稳定性分析揭示了 T 细胞激活过程中 LARP4 介导的 NFκB1 mRNA 稳定性
DOI：
10.1093/nar/gkaa643
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发表时间：
2020-09-04
影响因子：
14.9
通讯作者：
Zhu, Jun
中科院分区：
文献类型：
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作者：
Tian, Yi;Zeng, Zhouhao;Zhu, Jun
T细胞活化是研究细胞对外源性刺激的反应的成熟模型。受我们先前发现内含子保留（IR）可能导致转录不稳定性的启发，在这项研究中，我们进行了BruChase-Seq实验监测静息和活化的CD 4（+）T细胞中新生转录本的表达动态。然后应用计算建模在全基因组范围内量化剪接和内含子保留转录本的稳定性。除了证实内含子保留的转录本比剪接的转录本稳定性低得多之外，我们发现在T细胞活化后剪接的mRNA的整体稳定性，尽管内含子保留的转录本的稳定性保持相对恒定。此外，我们发现，La相关蛋白4（LARP 4），RNA结合蛋白（RBP）已知增强mRNA的稳定性，参与T细胞活化依赖的mRNA稳定。在小鼠中敲除Larp 4使Nf kappa b1 mRNA不稳定，并减少白细胞介素-2（IL 2）和干扰素-γ（IFN γ）的分泌，这两个因素对T细胞增殖和功能至关重要。我们建议剪接调控和mRNA稳定性之间的协调可能提供一个新的范例，以控制时空的基因表达在T细胞活化。
T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Motivated by our previous finding that intron retention (IR) could lead to transcript instability, in this study, we performed BruChase-Seq to experimentally monitor the expression dynamics of nascent transcripts in resting and activated CD4(+) T cells. Computational modeling was then applied to quantify the stability of spliced and intron-retained transcripts on a genome-wide scale. Beyond substantiating that intron-retained transcripts were considerably less stable than spliced transcripts, we found a global stabilization of spliced mRNAs upon T cell activation, although the stability of intron-retained transcripts remained relatively constant. In addition, we identified that La-related protein 4 (LARP4), an RNA-binding protein (RBP) known to enhance mRNA stability, was involved in T cell activation-dependent mRNA stabilization. Knocking out Larp4 in mice destabilized Nf kappa b1 mRNAs and reduced secretion of interleukin-2 (IL2) and interferon-gamma (IFN gamma), two factors critical for T cell proliferation and function. We propose that coordination between splicing regulation and mRNA stability may provide a novel paradigm to control spatiotemporal gene expression during T cell activation.