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Cited by 45Genomics and Chromatin DynamicsHematopoietic Stem Cell TransplantationEpigenetics and DNA Methylation

Chromatin-state barriers enforce an irreversible mammalian cell fate decision

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Blanco, M. Andrés, Sykes, David B., Gu, Lei, Wu, Mengjun, Petroni, Ricardo, Karnik, Rahul, Wawer, Mathias, Rico, Joshua +8 more·2021·Cell Reports
DOI 10.1016/j.celrep.2021.109967

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Abstract

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogate determinants of this "point of no return" in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identify potential avenues for manipulating cell identity.

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  • Development is fundamentally irreversible, providing a strong analogy for the irreversible changes that churn during chromosome and genome evolution.

    “Interestingly, development is fundamentally irreversible (181–183), providing a strong analogy for the irreversible changes that churn during chromosome and genome evolution.”

    From Topological Approaches in Animal Comparative Genomics (2026) · cites this paper as [182]

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Cited by

Sorted by citations

Authors
Blanco, M. A., Sykes, D. B., Gu, L., Wu, M., Petroni, R., Karnik, R., Wawer, M., Rico, J., Li, H., Jacobus, W. D., Jambhekar, A., Cheloufi, S., Meissner, A., Hochedlinger, K., Scadden, D. T., & Shi, Y.
Affiliations
  • Harvard University (US)
  • Boston Children's Hospital (US)
  • University of Pennsylvania (US)
  • Broad Institute (US)
  • University of California, Riverside (US)
Corresponding author
  • Scadden, David T.
  • Shi, Yang
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-11
Volume
37
Issue
6
Pages
109967
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.109967
OpenAlex
W3211895395
Cited by
45
References
10
Citations by year
2026: 8 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 12 · 2021: 1
FWCI
2.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by-nc-nd)
Funders
  • Boston Children's Hospital
  • Ludwig Institute for Cancer Research
  • National Institutes of Health (5R01HD058013-10)
  • Cancer Research Coordinating Committee (5P01GM099117)
  • National Cancer Institute
  • Deutsche Forschungsgemeinschaft (390649896, EXC 2026)
  • Max-Planck-Gesellschaft
  • Leukemia and Lymphoma Society (3353-15)
  • American Society of Hematology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
chromatin state, cell fate determination, myeloid progenitor cells, granulocytic differentiation, self-renewal, cellular plasticity, point of no return, hematopoiesis, cell identity
MeSH terms
Animals, Bone Marrow, Cell Differentiation, Cells, Cultured, Chromatin, Female, Hematopoiesis, Hematopoietic Stem Cells, Transcription Factors, Cell Lineage, Gene Expression Profiling, Myeloid Cells, Mice

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