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Changes in cell-cycle rate drive diverging cell fates

Nature Reviews Genetics volume 25, page 379 (2024)Cite this article

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Changes in the concentrations of transcription factors drive cells to commit to different fates. These concentration changes can be achieved through mechanisms such as transcriptional activation or protein degradation. However, the role of the cell cycle in regulating transcription factor levels and cell fate remains underappreciated. During differentiation, cells often divide before committing to divergent fates, enabling the generation of new cells and maintenance of a self-renewing progenitor population. Differences in the proliferation rate of these populations emerge as their fates diverge. Thus, it remains challenging to separate the role of the cell cycle in establishing cell identity from cell identity itself.

In 2013, to address how cell cycle influences the divergence of myeloid and lymphoid cells from a progenitor population, Kueh et al. examined how expression of the pioneer transcription factor PU.1 generated distinct cell fates in mice. At high levels, PU.1 positively regulates its own transcription to maintain myeloid identity in macrophages. Simultaneously, PU.1 reduces the cycling rate of myeloid cells. Increased transcription of Spi1, the gene encoding PU.1, might drive accumulation of PU.1 in progenitors, reinforcing expression and commitment to the myeloid fate. Alternatively, lengthening of the cell cycle may enable PU.1 to accumulate and drive commitment. To examine these competing models of cell-fate regulation, Kueh et al. established a transgenic mouse model with a bicistronic cassette including a fluorescent marker, PU.1–GFP. As PU.1–GFP levels mirror expression of endogenous PU.1, the rate of PU.1 synthesis can be monitored as cells transition from progenitors into B cells and macrophages.

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  • Babos, K. N. et al. Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming. Cell Stem Cell 25, 486–500 (2019)

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  1. Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Kate E. Galloway

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  1. Kate E. Galloway
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Correspondence to Kate E. Galloway.

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Galloway, K.E. Changes in cell-cycle rate drive diverging cell fates. Nat Rev Genet 25, 379 (2024). https://doi.org/10.1038/s41576-024-00714-0

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