Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation
Marioni, John C.
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Barile, M., Imaz-Rosshandler, I., Inzani, I., Ghazanfar, S., Nichols, J., Marioni, J. C., Guibentif, C., & et al. (2021). Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation. Genome Biology, 22 (1) https://doi.org/10.1186/s13059-021-02414-y
Abstract: Background: 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. Results: 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. Conclusions: 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.
Research, RNA velocity, Gastrulation, Erythropoiesis, Gata1
Wellcome Trust (105031/D/14/Z, 097922/Z/11/Z, 206328/Z/17/Z)
Royal Society (GB) (NIF\R1\181950)
Blood Cancer UK (GB) (18002)
Medical Research Council (MR/M008975/1, MR/S036113/1)
British Heart Foundation (FS/18/56/35177)
External DOI: https://doi.org/10.1186/s13059-021-02414-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330004