Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation.
Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation.
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基因表达动力学的协调变化是小鼠和人类红细胞成熟的基础。
DOI：
10.1186/s13059-021-02414-y
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发表时间：
2021-07-05
期刊：
影响因子：
12.3
通讯作者：
Göttgens B
中科院分区：
文献类型：
--
作者：
Barile M;Imaz-Rosshandler I;Inzani I;Ghazanfar S;Nichols J;Marioni JC;Guibentif C;Göttgens B
单细胞技术正在改变生物医学研究，包括最近证明单细胞 RNA-Seq 中存在的未剪接前 mRNA 可以预测未来的表达状态。在这里，我们将这种 RNA 速度概念应用于涵盖小鼠原肠胚形成和早期器官发生的扩展时间过程数据集。有趣的是，RNA 速度正确地将外胚层细胞识别为起点，但后期的一些轨迹预测与实时排序和现有知识不一致。最显着的差异涉及红细胞成熟，速度推断的轨迹与真正的分化路径相反。调查根本原因揭示了一组在转录中具有协调阶跃变化的基因，从而违反了当前速度分析套件背后的假设，该套件不适应表达动态的时间依赖性变化。通过对缺乏主要红系调节因子 Gata1 的嵌合小鼠胚胎进行 scRNA-Seq 分析，我们发现在红系分化过程中表达动态发生阶跃变化的基因未能在突变细胞中上调，从而强调了沿着分化轨迹调节转录速率的协调。除了预期的红细胞成熟受阻之外，Gata1-chimera 数据集还揭示了 PU.1 的诱导和巨核细胞祖细胞的扩增。最后，我们发现人类胎儿肝脏中的红细胞生成具有类似的特征，即基因表达的协调阶跃变化。通过确定当前速度框架的局限性以及突变细胞的体内分析，我们揭示了红细胞生成过程中基因表达动力学的协调阶跃变化，这可能对许多其他分化过程产生影响。在线版本包含可在 10.1186/s13059-021-02414-y 获取的补充材料。
Single-cell technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single-cell RNA-Seq permits prediction of future expression states. Here we apply this RNA velocity concept to an extended timecourse dataset covering mouse gastrulation and early organogenesis. Intriguingly, RNA velocity correctly identifies epiblast cells as the starting point, but several trajectory predictions at later stages are inconsistent with both real-time ordering and existing knowledge. The most striking discrepancy concerns red blood cell maturation, with velocity-inferred trajectories opposing the true differentiation path. Investigating the underlying causes reveals a group of genes with a coordinated step-change in transcription, thus violating the assumptions behind current velocity analysis suites, which do not accommodate time-dependent changes in expression dynamics. Using scRNA-Seq analysis of chimeric mouse embryos lacking the major erythroid regulator Gata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be upregulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. In addition to the expected block in erythroid maturation, the Gata1-chimera dataset reveals induction of PU.1 and expansion of megakaryocyte progenitors. Finally, we show that erythropoiesis in human fetal liver is similarly characterized by a coordinated step-change in gene expression. By identifying a limitation of the current velocity framework coupled with in vivo analysis of mutant cells, we reveal a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes. The online version contains supplementary material available at 10.1186/s13059-021-02414-y.
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影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
11.8
作者：
Guibentif C;Griffiths JA;Imaz-Rosshandler I;Ghazanfar S;Nichols J;Wilson V;Göttgens B;Marioni JC
通讯作者：
Marioni JC
影响因子：
12.3
作者：
Kim JK;Marioni JC
通讯作者：
Marioni JC
影响因子：
10.5
作者：
HIGGS, DR;WOOD, WG;AYYUB, H
通讯作者：
AYYUB, H
影响因子：
13.6
作者：
Akunuru S;Geiger H
通讯作者：
Geiger H