Coordinated changes in gene expression kinetics underlie both mouse and human erythroid maturation
Autor: | Melania Barile, Berthold Göttgens, Carolina Guibentif, John C. Marioni, Jennifer Nichols, Isabella Inzani, Shila Ghazanfar, Ivan Imaz-Rosshandler |
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Přispěvatelé: | Göttgens, Berthold [0000-0001-6302-5705], Apollo - University of Cambridge Repository |
Rok vydání: | 2021 |
Předmět: |
Transcriptional Activation
QH301-705.5 Organogenesis Gata1 Regulator Datasets as Topic QH426-470 Biology 03 medical and health sciences Mice 0302 clinical medicine Fetus Erythroid Cells Transcription (biology) Proto-Oncogene Proteins Gene expression Genetics Animals Humans GATA1 Transcription Factor Erythropoiesis Biology (General) Gene 030304 developmental biology 0303 health sciences Research Gastrulation RNA Gene Expression Regulation Developmental GATA1 Cell Differentiation Gastrula Embryo Mammalian Cell biology RNA velocity Kinetics Liver Epiblast 030220 oncology & carcinogenesis Trans-Activators Single-Cell Analysis |
Zdroj: | Genome Biology Genome Biology, Vol 22, Iss 1, Pp 1-22 (2021) |
DOI: | 10.17863/cam.77448 |
Popis: | 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. |
Databáze: | OpenAIRE |
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