Epigenetic Thpok silencing limits the time window to choose CD4+ helper-lineage fate in the thymus
Epigenetic Thpok silencing limits the time window to choose CD4+ helper-lineage fate in the thymus
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DOI：
10.1038/emboj.2013.47
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发表时间：
2013-04-17
期刊：
影响因子：
11.4
通讯作者：
Taniuchi, Ichiro
中科院分区：
文献类型：
--
作者：
Tanaka, Hirokazu;Naito, Taku;Taniuchi, Ichiro
在T细胞受体（TCR）介导的选择后，CD 4（+）辅助性和CD 8（+）细胞毒性T细胞从胸腺中的共同前体分化而来。辅助谱系的承诺取决于持续的TCR信号和ThPOK转录因子的表达，而ThPOK顺式调节元件，ThPOK沉默子，抑制Thpok基因的表达，在承诺的细胞毒性谱系。在这里，我们发现沉默子介导的细胞毒性系胸腺细胞染色质结构的改变建立了一种抑制状态，即使在去除沉默子后，这种抑制状态也会在外周CD 8（+）T细胞中表观遗传。当沉默子活性在辅助谱系细胞中通过增加其拷贝数而增强时，发生类似的可遗传的Thpok沉默。因此，表观遗传锁定的Thpok基因座可能是一个独立的事件，从承诺的细胞毒性谱系。这些发现意味着，需要持久的TCR信号来建立稳定的Thpok表达活性以致力于辅助性T细胞命运，并且完全致力于辅助性谱系需要在特定时间窗期间持续逆转沉默物活性。The EMBO Journal（2013）32，1183-1194. doi：10.1038/daj.2013.47; 2013年3月12日在线发布
CD4(+) helper and CD8(+) cytotoxic T cells differentiate from common precursors in the thymus after T-cell receptor (TCR)-mediated selection. Commitment to the helper lineage depends on persistent TCR signals and expression of the ThPOK transcription factor, whereas a ThPOK cis-regulatory element, ThPOK silencer, represses Thpok gene expression during commitment to the cytotoxic lineage. Here, we show that silencer-mediated alterations of chromatin structures in cytotoxic-lineage thymocytes establish a repressive state that is epigenetically inherited in peripheral CD8(+) T cells even after removal of the silencer. When silencer activity is enhanced in helper-lineage cells, by increasing its copy number, a similar heritable Thpok silencing occurs. Epigenetic locking of the Thpok locus may therefore be an independent event from commitment to the cytotoxic lineage. These findings imply that long-lasting TCR signals are needed to establish stable Thpok expression activity to commit to helper T-cell fate and that full commitment to the helper lineage requires persistent reversal of silencer activity during a particular time window. The EMBO Journal (2013) 32, 1183-1194. doi: 10.1038/emboj.2013.47; Published online 12 March 2013