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Published August 9, 2013 | Accepted Version + Supplemental Material
Journal Article Open

Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation


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.

Additional Information

© 2013 American Association for the Advancement of Science. Received 21 May 2013; accepted 5 July 2013 Published online 18 July 2013. We thank R. Butler and S. Washburn for mouse care and J. Verceles, J. Grimm, and D. Perez of the Caltech Flow Cytometry Facility for cell sorting. We also thank members of the Rothenberg and Elowitz labs and L. Goentoro for insightful discussions. The data presented in this manuscript are tabulated in the main paper and the supplementary materials. This work was supported by a Cancer Research Institute/Irvington Postdoctoral Fellowship to H.Y.K.; an Australian Research Council Future Fellowship and the Victorian State Government Operational Infrastructure Support, National Health and Medical Research Council of Australia Independent Research Institute Infrastructure Scheme to S.L.N.; NIH grants to E.V.R. (RC2 CA148278, R33 HL089123, R01 AI083514, and R01 CA90233); the Albert Billings Ruddock Professorship; the Al Sherman Foundation; and the Louis A. Garfinkle Memorial Laboratory Fund.

Attached Files

Accepted Version - nihms548960.pdf

Supplemental Material - Kueh.SM.pdf


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