Cell cycle controlling the silencing and functioning of mammalian activators
Cell cycle controlling the silencing and functioning of mammalian activators
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DOI：
10.1016/s0960-9822(01)00533-4
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发表时间：
2001-10-30
期刊：
影响因子：
9.2
通讯作者：
Reiner, SL
中科院分区：
文献类型：
--
作者：
Mullen, AC;Hutchins, AS;Reiner, SL
幼稚的CD4(+)辅助T(T-H)细胞通过终末分化为两个成熟的细胞，T(H)1细胞和T(H)2细胞，T(H)1细胞和T(H)2细胞表达白细胞介素4(IL-4)。转录激活剂T-bet[2，3]和GATA-3[4，5]分别介导对T(H)1和T(H)2命运的承诺，包括特征基因的染色质重塑。细胞因子IL-12促进T(H)1细胞的生长[3]，而IL-4促进T(H)2细胞的生长[6]。IL-12和IL-4也分别通过促进GATA-3[7]和T-bet[3]的转录沉默在承诺中发挥关键作用。我们现在证明T-bet和GATA-3在双能祖细胞中都是以细胞周期无关的方式被诱导的。相反，由激活子蛋白诱导的谱系限制性基因和每个激活子转录的可遗传沉默都是细胞周期依赖的。我们发现，不能循环的细胞对最两极分化的成熟信号做出反应时，仍然保持未确定的和双能的状态。这些结果提供了对哺乳动物末端分化模型的机械洞察，说明了最初在酵母[8，9]中描述的细胞周期耦合表观遗传效应可能代表了一种进化保守的组织信号和细胞命运的策略。
Naive 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) [1]. The transcriptional activators T-bet [2, 3] and Gata-3 [4, 5] 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 [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 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.