Cell cycle controlling the silencing and functioning of mammalian activators

Alan C. Mullen, Anne S. Hutchins, Alejandro V. Villarino, Hubert W. Lee, Frances A. High, Nezih Cereb, Soo Y. Yang, Xianxin Hua, Steven L. Reiner

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Naïve CD4+ helper T (TH) cells respond to stimulation by terminally differentiating into two mature classes, TH1 cells, which express interferon γ, (IFN-γ,), and TH2 cells, which express interleukin 4 (IL-4) [1]. The transcriptional activators T-bet [2, 3] and Gata-3 [4, 5] mediate commitment to the TH1 and TH2 fates, respectively, including chromatin remodeling of signature genes. The cytokine IL-12 fosters growth of committed TH1 cells [3], while IL-4 fosters growth of committed TH2 cells [6]. IL-12 and IL-4 also play critical roles in commitment by promoting transcriptional silencing of Gata-3 [7] and T-bet [3], 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 [8, 9], may represent an evolutionarily conserved strategy for organizing signaling and cell fate.

Original languageEnglish (US)
Pages (from-to)1695-1699
Number of pages5
JournalCurrent Biology
Volume11
Issue number21
DOIs
StatePublished - Oct 30 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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