CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus
CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus
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DOI：
10.1016/j.immuni.2008.02.006
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发表时间：
2008-03-01
期刊：
影响因子：
32.4
通讯作者：
Kappes, Dietmar J.
中科院分区：
文献类型：
--
作者：
He, Xi;Park, Kyewon;Kappes, Dietmar J.
转录因子 ThPOK 对于触发 CD4 淋巴细胞命运的采用是必要且充分的。在这里，我们研究了 ThPOK 表达的调节及其对 CD4(+) T 细胞定向的后续控制。用抗TCR IT细胞受体处理未成熟胸腺细胞表明TCR信号在ThPOK诱导中很重要并且CD4(+)8(lo)阶段是诱导TCR信号的可能目标。我们在 ThPOK 基因座上鉴定了一个关键的远端调节元件 (DRE)，该元件介导其在 I 类与 II 类限制性 CD4(+)8(lo) 胸腺细胞中的差异表达。 DRE 既是 I 类限制性胸腺细胞中抑制 ThPOK 表达所必需的，又足以在 II 类限制性胸腺细胞中诱导 ThPOK 表达。诱变分析确定了必需的 80bp 核心 DRE 序列及其潜在的调控基序。我们提出了一种依赖于沉默子的谱系选择模型，其中强 TCR 信号使 DRE 沉默子失活导致 CD4 承诺，而持续的沉默子活动导致 CD8 承诺。
The transcription factor ThPOK is necessary and sufficient to trigger adoption of the CD4 lymphocyte fate. Here we investigate the regulation of ThPOK expression and its subsequent control of CD4(+) T cell commitment. Treatment of immature thymocytes with anti-TCR IT cell receptor) showed that TCR signals were important in ThPOK induction and that the CD4(+)8(lo) stage was the likely target of the inductive TCR signal. We identified at the ThPOK locus a key distal regulatory element (DRE) that mediated its differential expression in class I- versus II-restricted CD4(+)8(lo) thymocytes. The DRE was both necessary for suppression of ThPOK expression in class I-restricted thymocytes and sufficient for its induction in class II-restricted thymocytes. Mutagenesis analysis defined an essential 80bp core DRE sequence and its potential regulatory motifs. We propose a silencer-dependent model of lineage choice, whereby inactivation of the DRE silencer by a strong TCR signal leads to CD4 commitment, whereas continued silencer activity leads to CD8 commitment.