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Cited by 88Gene Regulatory Network AnalysisSingle-cell and spatial transcriptomicsDevelopmental Biology and Gene Regulation

Single-molecule imaging of transcription dynamics in somatic stem cells

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Wheat, Justin C., Sella, Yehonatan, Willcockson, Michael, Skoultchi, Arthur I., Bergman, Aviv, Singer, Robert H., Steidl, Ulrich·2020·Nature
DOI 10.1038/s41586-020-2432-4PMC PMC8577313
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Abstract

Molecular noise is a natural phenomenon that is inherent to all biological systems 1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states-akin to a transcriptional priming phenomenon-the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness.

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  • Key hematopoietic TFs are expressed in smooth, overlapping gradients throughout stem and progenitor populations, whereas their target genes display cell-state-specific expression patterns.

    “single-cell transcriptomics1,2,3 and imaging-based4 studies have demonstrated that key TFs are expressed in smooth, overlapping gradients throughout the stem and progenitor populations (Figure 1A, top row); by contrast, the target genes regulated by these factors display cell-state-specific expression patterns (Figure 1A, bottom row).”

    From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [4]

    The “PU.1 and Gata TF co-expression in HSPC” section reports substantial co-expression across the progenitor populations studied, and “Single molecule imaging in primary HSPC” reports different transcription of myeloid and erythroid genes in PU.1-high cells. These passages support overlapping TF expression and state-associated differences in selected genes, but do not establish smooth gradients throughout stem and progenitor populations or cell-state-specific expression patterns for target genes generally. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • 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 Wheat et al., 2020

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Cites

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Research works printed but not linked: 29

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Cited by

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Authors
Wheat, J. C., Sella, Y., Willcockson, M., Skoultchi, A. I., Bergman, A., Singer, R. H., & Steidl, U.
Affiliations
Albert Einstein College of Medicine (US)
Corresponding author
Steidl, Ulrich
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-06-24
Volume
583
Issue
7816
Pages
431-436
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2432-4
PMC
PMC8577313
OpenAlex
W3037155407
Cited by
88
References
12
Citations by year
2026: 10 · 2025: 12 · 2024: 12 · 2023: 20 · 2022: 13 · 2021: 18 · 2020: 3
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL139487)
  • National Institute on Drug Abuse (U01DA047729)
  • National Cancer Institute (R01CA217092, P30CA013330)
  • National Institute of General Medical Sciences (F30GM122308, R01GM116143, T32GM007288)
  • National Institute of Neurological Disorders and Stroke (R01NS083085)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
transcriptional noise, adult stem cells, hematopoietic stem and progenitor cells, PU.1, GATA-1, GATA2, transcriptional bursting, stochastic gene expression, transcriptional priming, transcriptional plasticity, stem cell heterogeneity, tissue homeostasis, lineage tracing
MeSH terms
Single Molecule Imaging, Proto-Oncogene Protein Spi-1, Animals, Cells, Cultured, Clone Cells, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Pedigree, Proto-Oncogene Proteins, RNA, Messenger, Stochastic Processes, Transcription, Genetic, Trans-Activators, In Situ Hybridization, Fluorescence, GATA1 Transcription Factor, GATA2 Transcription Factor, Mice, Gene Regulatory Networks, Adult Stem Cells

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