Department of Immunology, Technion-Israel Institute of Technology, Haifa, Israel.
Eur J Immunol. 2011 Aug;41(8):2424-35. doi: 10.1002/eji.201141620. Epub 2011 Jul 4.
We have previously shown that in differentiated T-helper (Th)1 and Th2 cells, polycomb group (PcG) proteins are associated differentially with the promoters of the signature cytokine genes. The correlation of the binding activity of PcG proteins with gene expression is unusual, since they are well known as epigenetic regulators that maintain transcriptional silencing. Here we show that in Th17 cells, the more phenotypically flexible Th lineage, the PcG proteins Mel-18 and less strikingly Ezh2 are associated differentially with the Il17a promoter. Using the RNAi approach, we found that Mel-18 and Ezh2 positively regulate the expression of Il17a and Il17f. The inducible binding of Mel-18 and Ezh2 at the Il17a promoter was dependent on signaling pathways downstream of the TCR. However, a continuous presence of TGF-β, the cytokine that is necessary to maintain Il17a expression, was required to preserve the binding activity of Mel-18, but not of Ezh2, following restimulation. The binding of Mel-18 at the Il17a promoter was correlated with the recruitment of the lineage-specifying transcription factor RORγt. Altogether, our results suggest that in Th17 cells the TCR and polarizing cytokines synergize to modulate the binding activity of Mel-18 at the Il17a promoter, and consequently to facilitate Il17a expression.
我们之前已经证明，在分化的 T 辅助（Th）1 和 Th2 细胞中，多梳组（PcG）蛋白与特征细胞因子基因的启动子的结合存在差异。PcG 蛋白的结合活性与基因表达的相关性是不寻常的，因为它们是众所周知的表观遗传调节剂，可维持转录沉默。在这里，我们表明在 Th17 细胞中，这种表型更为灵活的 Th 谱系中，PcG 蛋白 Mel-18 和不太明显的 Ezh2 与 Il17a 启动子的结合存在差异。使用 RNAi 方法，我们发现 Mel-18 和 Ezh2 可正向调节 Il17a 和 Il17f 的表达。Mel-18 和 Ezh2 在 Il17a 启动子上的诱导性结合依赖于 TCR 下游的信号通路。然而，在重新刺激后，TGF-β的持续存在是必需的，TGF-β是维持 Il17a 表达所必需的细胞因子，可维持 Mel-18 的结合活性，但不能维持 Ezh2 的结合活性。Mel-18 在 Il17a 启动子上的结合与谱系特异性转录因子 RORγt 的募集相关。总之，我们的结果表明，在 Th17 细胞中，TCR 和极化细胞因子协同作用来调节 Mel-18 在 Il17a 启动子上的结合活性，从而促进 Il17a 的表达。
