Cell cycle controlling the silencing and functioning of mammalian activators

Naive CD4(+) helper T (T-H) cells respond to stimulation by terminally diff erentiating 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) [1]. The transcriptional activators T-bet [2, 3] and Gata-3 [4, 5] mediate comm itment to the T(H)1 and T(H)2 fates, respectively, including chromatin remo deling of signature genes. The cytokine IL-12 fosters growth of committed T (H)1 cells [3], while IL-4 fosters growth of committed T(H)2 cells [6]. IL- 12 and IL-4 also play critical roles in commitment by promoting transcripti onal 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 bip otent 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 d ependent. We found that cells that cannot cycle remain uncommitted and bipo tent in response to the most polarizing signals for maturation. These resul ts provide mechanistic insight into a mammalian model of terminal different iation by illustrating that cell cycle-coupled epigenetic effects, as origi nally described in yeast [8, 9], may represent an evolutionarily conserved strategy for organizing signaling and cell fate.