Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate
Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate
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DOI：
10.1038/ni.1650
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发表时间：
2008-10-01
影响因子：
30.5
通讯作者：
Taniuchi, Ichiro
中科院分区：
文献类型：
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作者：
Muroi, Sawako;Naoe, Yoshinori;Taniuchi, Ichiro
CD4和转录因子ThPOK是主要组织相容性复合体II类限制性胸腺细胞向辅助性T细胞谱系分化所必需的；它们的基因（Cd4和Zbtb7b（这里称为“ThPOK”））被细胞毒性T细胞中的转录沉默元件抑制。在辅助性T细胞谱系分化过程中调控这些基因表达的分子机制尚不清楚。在这里，我们发现，通过从ThPOK位点去除近端增强子，诱导ThPOK的低效上调，导致辅助谱系指定的细胞转分化为细胞毒性T细胞谱系。此外，ThPOK对Cd4和ThPOK沉默子的直接拮抗产生了两个调控回路，最初抑制Cd4下调，后来稳定ThPOK的表达。我们的研究结果表明，在谱系承诺过程中，初始谱系规范信号可以被放大和稳定。
CD4 and the transcription factor ThPOK are essential for the differentiation of major histocompatibility complex class II restricted thymocytes into the helper T cell lineage; their genes (Cd4 and Zbtb7b (called 'ThPOK' here)) are repressed by transcriptional silencer elements in cytotoxic T cells. The molecular mechanisms regulating expression of these genes during helper T cell lineage differentiation remain unknown. Here we showed that inefficient upregulation of ThPOK, induced by removal of the proximal enhancer from the ThPOK locus, resulted in the transdifferentiation of helper lineage-specified cells into the cytotoxic T cell lineage. Furthermore, direct antagonism by ThPOK of the Cd4 and ThPOK silencers generated two regulatory loops that initially inhibited Cd4 downregulation and later stabilized ThPOK expression. Our results show how an initial lineage-specification signal can be amplified and stabilized during the lineage-commitment process.