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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene
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Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene

机译：转录因子AP4调节Cd4基因的可逆和表观遗传沉默

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摘要

CD4 coreceptor expression is negatively regulated through activity of the Cd4 silencer in CD4~CD8~ double-negative (DN) thymocytes and CD8+ cytotoxic lineage T cells. Whereas Cd4 silencing is reversed during transition from DN to CD4+CD8+ double-positive stages, it is maintained through heritable epigenetic processes following its establishment in mature CD8+ T cells. We previously demonstrated that the Runx family of transcription factors is required for Cd4 silencing both in DN thymocytes and CD8+ T cells. However, additional factors that cooperate with Runx proteins in the process of Cd4 silencing remain unknown. To identify collaborating factors, we used microarray and RNAi-based approaches and found the basic helix-loop-helix ZIP transcription factor AP4 to have an important role in Cd4 regulation. AP4 interacts with Runxi in cells in which Cd4 is silenced, and is required for Cd4 silencing in immature DN thymocytes through binding to the proximal enhancer. Furthermore, although AP4-deficient CD8+ T cells appeared to normally down-regulate CD4 expression, AP4 deficiency significantly increased the frequency of CD4-expressing effector/memory CD8+ T cells in mice harboring point mutations in the Cd4 silencer. Our results suggest that AP4 contributes to Cd4 silencing both in DN and CD8+ T cells by enforcing checkpoints for appropriate timing of CD4 expression and its epigenetic silencing.
机译：CD4受体的表达受CD4〜CD8〜双阴性（DN）胸腺细胞和CD8 +细胞毒性谱系T细胞中Cd4沉默子活性的负调控。 Cd4沉默在从DN过渡到CD4 + CD8 +双重阳性阶段的过程中逆转，而在成熟的CD8 + T细胞中建立后，通过可遗传的表观遗传过程得以维持。我们先前证明，DN胸腺细胞和CD8 + T细胞中Cd4沉默都需要Runx转录因子家族。但是，在Cd4沉默过程中与Runx蛋白协同作用的其他因素仍然未知。为了确定协作因素，我们使用了基于微阵列和基于RNAi的方法，发现基本的螺旋-环-螺旋ZIP转录因子AP4在Cd4调控中具有重要作用。在Cd4沉默的细胞中，AP4与Runxi相互作用，并且是通过与近端增强子结合而使未成熟DN胸腺细胞中Cd4沉默所必需的。此外，尽管缺乏AP4的CD8 + T细胞似乎正常下调了CD4的表达，但AP4缺乏显着增加了在Cd4沉默子中带有点突变的小鼠中表达CD4的效应子/记忆CD8 + T细胞的频率。我们的结果表明，AP4通过加强CD4表达的适当时机及其后生沉默的检查点，有助于DN和CD8 + T细胞中Cd4沉默。

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