title: Positive feedback between PU.1 and the cell cycle controls myeloid differentiation.
abstract: 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA, USA. kueh@caltech.edu
authors.forename: Hao Yuan
authors.initials: HY
authors.lastname: Kueh
authors.forename: Ameya
authors.initials: A
authors.lastname: Champhekar
authors.forename: Ameya
authors.initials: A
authors.lastname: Champhekhar
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D022423:Myeloid Cells / Q000166:cytology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1