Analysis of the inhibitory mechanisms of IFN gamma induced gene expression by hypoxia

我们先前已经证明，缺氧下调了干扰素诱导的人类肿瘤细胞系中趋化因子CXCL9和CXCL10基因的表达。我们探索了低氧下调干扰素诱导基因表达的机制，发现虽然HIF-1不参与干扰素诱导基因的转录抑制，但在低氧条件下，Pol II和辅活化子SRC-1的募集受到抑制。在这项研究中，我们研究了HIF-2、CXCL9基因启动子区域的组蛋白甲基化以及参与Pol II招募的介体复合体在低氧介导的转录抑制中的潜在参与。在HEK293细胞中过表达活性形式的HIF-2抑制了CXCL9启动子的活性，表明HIF-2负调控CXCL9的表达。实时荧光定量RT-PCR分析显示，HSC-2细胞中存在甲基转移酶和介体复合体的组成性表达。

We have previously shown that hypoxia down-regulated the IFN-induced expression of chemokine CXCL9 and CXCL10 genes in human tumor cell lines. We have explored the mechanisms by which hypoxia down-regulates the IFN-induced gene expressions and found that although HIF-1 was not involved in the transcriptional repression of the IFN-induced genes, recruitments of Pol II, coactivator SRC-1 were inhibited under the hypoxia. In this study, we investigated potential involvements of HIF-2, histone methylation at the promoter region of the CXCL9 genes, and mediator complex that participates in the recruitment of Pol II for the hypoxia-mediated transcriptional repression. Over expression of an active form of HIF-2 in HEK293 cells inhibited the CXCL9 promoter activity, suggesting that HIF-2 negatively regulates CXCL9 expression. Real-time RT-PCR analysis showed that constitutive expressions of mRNAs for methyltransferase and members of mediator complex were observed in HSC-2 cells.