Lineage marker synchrony in hematopoietic genealogies refutes the PU.1/GATA1 toggle switch paradigm
Open accessAbstract
Molecular regulation of cell fate decisions underlies health and disease. To identify molecules that are active or regulated during a decision, and not before or after, the decision time point is crucial. However, cell fate markers are usually delayed and the time of decision therefore unknown. Fortunately, dividing cells induce temporal correlations in their progeny, which allow for retrospective inference of the decision time point. We present a computational method to infer decision time points from correlated marker signals in genealogies and apply it to differentiating hematopoietic stem cells. We find that myeloid lineage decisions happen generations before lineage marker onsets. Inferred decision time points are in agreement with data from colony assay experiments. The levels of the myeloid transcription factor PU.1 do not change during, but long after the predicted lineage decision event, indicating that the PU.1/GATA1 toggle switch paradigm cannot explain the initiation of early myeloid lineage choice.
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PU.1 can engage in competitive interactions with transcriptional regulators such as GATA1 to promote myeloid differentiation.
“PU.1 can also engage in competitive interactions with transcriptional regulators such as GATA1 to promote myeloid differentiation (Strasser et al., 2018; Wheat et al., 2020; Raghav and Gangenahalli, 2021).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Strasser et al., 2018
The Results section describes PU.1 and GATA1 as mutually binding and cross-antagonistic, and says PU.1 is important in executing the granulocyte-macrophage lineage program. But it rejects the idea that their competitive toggle initiates lineage choice: PU.1 is described as an effector that locks down an already chosen lineage, not the driver of that choice. (LLM, conf=0.87)
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- Authors
- Strasser, M. K., Hoppe, P. S., Loeffler, D., Kokkaliaris, K. D., Schroeder, T., Theis, F. J., & Marr, C.
- Affiliations
- Helmholtz Munich (DE)
- ETH Zurich (CH)
- Corresponding author
- Marr, Carsten
- ORCID
- Venue
- Nature Communications
- Published
- 2018-07-12
- Volume
- 9
- Issue
- 1
- Pages
- 2697-2697
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6043612
- OpenAlex
- W2871741525
- Cited by
- 26
- References
- 58
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 1
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (MA 5282/3-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- hematopoietic stem cell differentiation, PU.1, GATA-1, genealogy, colony assay
- MeSH terms
- Proto-Oncogene Protein Spi-1, Algorithms, Animals, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Models, Biological, Proto-Oncogene Proteins, Time Factors, Trans-Activators, Cell Lineage, Computational Biology, Myeloid Cells, GATA1 Transcription Factor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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