Cheng, Y-C and Zhang, Y and Tripathi, S and Harshavardhan, BV and Jolly, MK and Schiebinger, G and Levine, H and McDonald, TO and Michor, F (2024) Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to- mesenchymal transition. In: Proceedings of the National Academy of Sciences of the United States of America, 121 (32).
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Abstract
Exploring the complexity of the epithelial-to- mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta- induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories. © 2024 the Author(s).
| Item Type: | Journal Article |
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| Publication: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| Additional Information: | The copyright for this article belongs to the authors. |
| Keywords: | transforming growth factor beta; transcription factor EZH2, apoptosis; Article; CDH1 gene; CDH2 gene; cell fate; cell heterogeneity; cell plasticity; cell proliferation; cell stemness; CENPF gene; CKS1B gene; cluster analysis; controlled study; differential gene expression; down regulation; EED gene; epithelial mesenchymal transition; EZH2 gene; gene; gene expression level; gene set enrichment analysis; growth rate; human; human cell; ITGB4 gene; KRT8 gene; LAMA3 gene; LAMB3 gene; MCF-10A cell line; MKI67 gene; POSTN gene; single cell RNA seq; upregulation; cell lineage; genetics; metabolism; procedures; single cell analysis, Cell Lineage; Enhancer of Zeste Homolog 2 Protein; Epithelial-Mesenchymal Transition; Humans; Single-Cell Analysis; Transforming Growth Factor beta |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering Division of Interdisciplinary Sciences > Interdisciplinary Mathematical Sciences |
| Date Deposited: | 28 Aug 2024 10:33 |
| Last Modified: | 28 Aug 2024 10:33 |
| URI: | http://eprints.iisc.ac.in/id/eprint/86008 |
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