title: Cell cycle controlling the silencing and functioning of mammalian activators.
abstract: Naïve CD4(+) helper T (T(H)) cells respond to stimulation by terminally differentiating into two mature classes, T(H)1 cells, which express interferon gamma (IFN-gamma), and T(H)2 cells, which express interleukin 4 (IL-4). The transcriptional activators T-bet and Gata-3 mediate commitment to the T(H)1 and T(H)2 fates, respectively, including chromatin remodeling of signature genes. The cytokine IL-12 fosters growth of committed T(H)1 cells, while IL-4 fosters growth of committed T(H)2 cells. IL-12 and IL-4 also play critical roles in commitment by promoting transcriptional silencing of Gata-3 and T-bet, respectively. We now show that both T-bet and Gata-3 are induced in a cell cycle-independent manner in bipotent progenitor cells. In contrast, both lineage-restricted gene induction by the activator proteins and heritable silencing of the transcription of each activator, the hallmarks of terminal differentiation, are cell cycle dependent. We found that cells that cannot cycle remain uncommitted and bipotent in response to the most polarizing signals for maturation. These results provide mechanistic insight into a mammalian model of terminal differentiation by illustrating that cell cycle-coupled epigenetic effects, as originally described in yeast, may represent an evolutionarily conserved strategy for organizing signaling and cell fate.
authors.affiliation: Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Mullen
authors.forename: A S
authors.initials: AS
authors.lastname: Hutchins
authors.forename: A V
authors.initials: AV
authors.lastname: Villarino
authors.forename: H W
authors.initials: HW
authors.lastname: Lee
authors.forename: F A
authors.initials: FA
authors.lastname: High
authors.forename: N
authors.initials: N
authors.lastname: Cereb
authors.forename: S Y
authors.initials: SY
authors.lastname: Yang
authors.forename: X
authors.initials: X
authors.lastname: Hua
authors.forename: S L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050990:GATA3 Transcription Factor; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018448:Models, Immunological; D020825:T-Box Domain Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma