Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved]
Background: Single-cell studies have demonstrated the presence of significant cell-to-cell heterogeneity in gene expression. Whether such heterogeneity is only a bystander or has a functional role in the cell differentiation process is still hotly debated. Methods: In this study, we quantified and f...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
F1000 Research Ltd
2023-07-01
|
| Series: | F1000Research |
| Subjects: | |
| Online Access: | https://f1000research.com/articles/12-426/v2 |
| _version_ | 1797755145056944128 |
|---|---|
| author | Rudiyanto Gunawan András Páldi Ulysse Herbach Nan Papili Gao Olivier Gandrillon |
| author_facet | Rudiyanto Gunawan András Páldi Ulysse Herbach Nan Papili Gao Olivier Gandrillon |
| author_sort | Rudiyanto Gunawan |
| collection | DOAJ |
| description | Background: Single-cell studies have demonstrated the presence of significant cell-to-cell heterogeneity in gene expression. Whether such heterogeneity is only a bystander or has a functional role in the cell differentiation process is still hotly debated. Methods: In this study, we quantified and followed single-cell transcriptional uncertainty – a measure of gene transcriptional stochasticity in single cells – in 10 cell differentiation systems of varying cell lineage progressions, from single to multi-branching trajectories, using the stochastic two-state gene transcription model. Results: By visualizing the transcriptional uncertainty as a landscape over a two-dimensional representation of the single-cell gene expression data, we observed universal features in the cell differentiation trajectories that include: (i) a peak in single-cell uncertainty during transition states, and in systems with bifurcating differentiation trajectories, each branching point represents a state of high transcriptional uncertainty; (ii) a positive correlation of transcriptional uncertainty with transcriptional burst size and frequency; (iii) an increase in RNA velocity preceding the increase in the cell transcriptional uncertainty. Conclusions: Our findings suggest a possible universal mechanism during the cell differentiation process, in which stem cells engage stochastic exploratory dynamics of gene expression at the start of the cell differentiation by increasing gene transcriptional bursts, and disengage such dynamics once cells have decided on a particular terminal cell identity. Notably, the peak of single-cell transcriptional uncertainty signifies the decision-making point in the cell differentiation process. |
| first_indexed | 2024-03-12T17:42:36Z |
| format | Article |
| id | doaj.art-502a6245c2fb4bffb5ab35093c4a27c8 |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-03-12T17:42:36Z |
| publishDate | 2023-07-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-502a6245c2fb4bffb5ab35093c4a27c82023-08-04T00:00:01ZengF1000 Research LtdF1000Research2046-14022023-07-0112153194Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved]Rudiyanto Gunawan0https://orcid.org/0000-0002-6480-7976András Páldi1Ulysse Herbach2https://orcid.org/0000-0002-0972-385XNan Papili Gao3Olivier Gandrillon4https://orcid.org/0000-0002-3676-6513Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Zurich, 8093, SwitzerlandSt-Antoine Research Center, Ecole Pratique des Hautes Etudes PSL, Paris, F-75012, FranceCNRS, Inria, IECL, Université de Lorraine, Nancy, F-54000, FranceInstitute for Chemical and Bioengineering, ETH Zurich, Zurich, Zurich, 8093, SwitzerlandLaboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS, Université Claude Bernard Lyon 1, F69364, FranceBackground: Single-cell studies have demonstrated the presence of significant cell-to-cell heterogeneity in gene expression. Whether such heterogeneity is only a bystander or has a functional role in the cell differentiation process is still hotly debated. Methods: In this study, we quantified and followed single-cell transcriptional uncertainty – a measure of gene transcriptional stochasticity in single cells – in 10 cell differentiation systems of varying cell lineage progressions, from single to multi-branching trajectories, using the stochastic two-state gene transcription model. Results: By visualizing the transcriptional uncertainty as a landscape over a two-dimensional representation of the single-cell gene expression data, we observed universal features in the cell differentiation trajectories that include: (i) a peak in single-cell uncertainty during transition states, and in systems with bifurcating differentiation trajectories, each branching point represents a state of high transcriptional uncertainty; (ii) a positive correlation of transcriptional uncertainty with transcriptional burst size and frequency; (iii) an increase in RNA velocity preceding the increase in the cell transcriptional uncertainty. Conclusions: Our findings suggest a possible universal mechanism during the cell differentiation process, in which stem cells engage stochastic exploratory dynamics of gene expression at the start of the cell differentiation by increasing gene transcriptional bursts, and disengage such dynamics once cells have decided on a particular terminal cell identity. Notably, the peak of single-cell transcriptional uncertainty signifies the decision-making point in the cell differentiation process.https://f1000research.com/articles/12-426/v2single cell gene expression cell differentiation transcriptional uncertainty RNA velocityeng |
| spellingShingle | Rudiyanto Gunawan András Páldi Ulysse Herbach Nan Papili Gao Olivier Gandrillon Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] F1000Research single cell gene expression cell differentiation transcriptional uncertainty RNA velocity eng |
| title | Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] |
| title_full | Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] |
| title_fullStr | Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] |
| title_full_unstemmed | Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] |
| title_short | Single-cell transcriptional uncertainty landscape of cell differentiation [version 2; peer review: 2 approved] |
| title_sort | single cell transcriptional uncertainty landscape of cell differentiation version 2 peer review 2 approved |
| topic | single cell gene expression cell differentiation transcriptional uncertainty RNA velocity eng |
| url | https://f1000research.com/articles/12-426/v2 |
| work_keys_str_mv | AT rudiyantogunawan singlecelltranscriptionaluncertaintylandscapeofcelldifferentiationversion2peerreview2approved AT andraspaldi singlecelltranscriptionaluncertaintylandscapeofcelldifferentiationversion2peerreview2approved AT ulysseherbach singlecelltranscriptionaluncertaintylandscapeofcelldifferentiationversion2peerreview2approved AT nanpapiligao singlecelltranscriptionaluncertaintylandscapeofcelldifferentiationversion2peerreview2approved AT oliviergandrillon singlecelltranscriptionaluncertaintylandscapeofcelldifferentiationversion2peerreview2approved |