Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene
Transcription factor AP4 modulates reversible and epigenetic silencing of the Cd4 gene
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DOI：
10.1073/pnas.1112293108
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发表时间：
2011-09-06
影响因子：
11.1
通讯作者：
Littman, Dan R.
中科院分区：
文献类型：
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作者：
Egawa, Takeshi;Littman, Dan R.
在CD4（-）、CD8（-）双阴性胸腺细胞和CD8（+）细胞毒谱系T细胞中，CD4沉默子的活性可负调控CD4辅助受体的表达。虽然Cd4沉默在从DN到Cd4 (+)CD8（+）双阳性阶段的转变过程中被逆转，但在成熟的CD8(+) T细胞中建立后，它通过可遗传的表观遗传过程得以维持。我们之前已经证明，在DN胸腺细胞和CD8(+) T细胞中，转录因子Runx家族是Cd4沉默所必需的。然而，在Cd4沉默过程中与Runx蛋白合作的其他因素仍然未知。为了确定协同因子，我们使用了微阵列和基于rnai的方法，发现基本的螺旋-环-螺旋ZIP转录因子AP4在Cd4调节中起重要作用。AP4在Cd4沉默的细胞中与Runx1相互作用，并且通过与近端增强子结合来沉默未成熟DN胸腺细胞中的Cd4。此外，尽管AP4缺陷的CD8(+) T细胞似乎正常下调CD4表达，但AP4缺陷显著增加了CD4沉默点突变小鼠中表达CD4的效应/记忆性CD8(+) T细胞的频率。我们的研究结果表明，AP4在DN和CD8(+) T细胞中通过加强适当的Cd4表达时间和其表观遗传沉默的检查点来促进Cd4沉默。
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 Runx1 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.