Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation.
Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation.
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DOI：
10.1016/j.molcel.2017.06.003
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发表时间：
2017-07-06
期刊：
影响因子：
16
通讯作者：
Yeo GW
中科院分区：
文献类型：
--
作者：
Song Y;Botvinnik OB;Lovci MT;Kakaradov B;Liu P;Xu JL;Yeo GW
选择性剪接（AS）产生异构体多样性的细胞身份和稳态在多细胞生活。尽管在单个细胞中观察到AS变异，但对这种变异的生物学或进化意义知之甚少。我们开发了Expedition，一个计算框架，包括支腿，从头拼接图横向算法来检测AS;锚，贝叶斯方法来分配模态和bonvoyage，一个可视化工具，使用非负矩阵分解来显示模态变化。将Expedition应用于经历神经元分化的单个多能干细胞，我们发现高达20%的AS外显子表现出双峰性。双峰外显子两侧是保守的内含子序列，具有不同的顺式调控基序，构成了许多细胞类型特异性剪接，在细胞转换过程中高度动态，保留阅读框架，并揭示了传统基因表达分析不可见的细胞状态的复杂性。单细胞系统AS表征重新定义了我们对细胞生物学中AS复杂性的理解。
Alternative splicing (AS) generates isoform diversity for cellular identity and homeostasis in multicellular life. Although AS variation has been observed among single cells, little is known about the biological or evolutionary significance of such variation. We developed Expedition, a computational framework consisting of outrigger, a de novo splice graph transversal algorithm to detect AS; anchor, a Bayesian approach to assign modalities and bonvoyage, a visualization tool using non-negative matrix factorization to display modality changes. Applying Expedition to single pluripotent stem cells undergoing neuronal differentiation, we discover that up to 20% of AS exons exhibit bimodality. Bimodal exons are flanked by more conserved intronic sequences harboring distinct cis-regulatory motifs, constitute much of cell-type specific splicing, are highly dynamic during cellular transitions, preserve reading frame and reveal intricacy of cell states invisible to conventional gene expression analysis. Systematic AS characterization in single cells redefines our understanding of AS complexity in cell biology.
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影响因子：
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作者：
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通讯作者：
Kingsford, Carl
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影响因子：
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作者：
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