Journal
SCIENCE
Volume 341, Issue 6146, Pages 670-673Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1240831
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Funding
- Cancer Research Institute/Irvington Postdoctoral Fellowship
- Australian Research Council Future Fellowship
- Victorian State Government Operational Infrastructure Support
- National Health and Medical Research Council of Australia Independent Research Institute Infrastructure Scheme
- NIH [RC2 CA148278, R33 HL089123, R01 AI083514, R01 CA90233]
- Albert Billings Ruddock Professorship
- Al Sherman Foundation
- Louis A. Garfinkle Memorial Laboratory Fund
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Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle-coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.
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