title: Controlling low rates of cell differentiation through noise and ultrahigh feedback.
abstract: Mammalian tissue size is maintained by slow replacement of de-differentiating and dying cells. For adipocytes, key regulators of glucose and lipid metabolism, the renewal rate is only 10% per year. We used computational modeling, quantitative mass spectrometry, and single-cell microscopy to show that cell-to-cell variability, or noise, in protein abundance acts within a network of more than six positive feedbacks to permit pre-adipocytes to differentiate at very low rates. This reconciles two fundamental opposing requirements: High cell-to-cell signal variability is needed to generate very low differentiation rates, whereas low signal variability is needed to prevent differentiated cells from de-differentiating. Higher eukaryotes can thus control low rates of near irreversible cell fate decisions through a balancing act between noise and ultrahigh feedback connectivity.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ahrends
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Asuka
authors.initials: A
authors.lastname: Ota
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Kovary
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Byung Ouk
authors.initials: BO
authors.lastname: Park
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA. mteruel@stanford.edu.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Teruel
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D002460:Cell Line; D003198:Computer Simulation; D025461:Feedback, Physiological; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D059010:Single-Cell Analysis; D013234:Stem Cells / Q000166:cytology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering