Molecular mechanisms underlying the epigenetic dysregulation by synovial sarcoma specific fusion oncoprotein

我们一直在试图揭示滑膜肉瘤（SSs）中FZD10基因转录失调的分子机制，并发现FZD10启动子区域的组蛋白乙酰化与SSs中FZD10的上调密切相关。因此，我们下一步的目标是确定与此相关的组蛋白乙酰转移酶（HAT）。通过下拉实验和Western blotting，我们成功地鉴定出两个hat（命名为ssi1和2）是SS18-SSX的相互作用因子。此外，通过使用SSIH1和SSIH2的显性阴性（DN）形式，我们已经证明了SS细胞中SSIH（DN）的异位表达可以消除FZD10的表达。这一结果表明，SSIH1和SSIH2在功能上参与了SSs中FZD10的上调，但ChIP实验显示，体内只有SSHI1占据了FZD10的启动子区域。总的来说，我们已经确定了sss1是导致FZD10失调的HAT。

We have been trying to unravel the molecular mechanism underlying the transcriptional dysregulation of FZD10 gene in synovial sarcomas (SSs) and have found that histone acetylation of the promoter region of FZD10 strongly correlates with up-regulation of FZD10 in SS. So, we next aimed to identify the histone acetyltransferase (HAT) responsible for this. By adopting pull-down assay followed by Western blotting, we succeeded to identify two HATs (designated as SSIH1 and 2) as the interactors of SS18-SSX. Furthermore, by using dominant-negative (DN) forms of SSIH1 and SSIH2, we have demonstrated that ectopic expression of SSIH(DN) in SS cells abrogated the expression of FZD10. This result indicates SSIH1 and SSIH2 are functionally involved in up-regulation of FZD10 in SSs, However, ChIP assay revealed that only SSHI1 occupies the FZD10 promoter region in vivo. Collectively, We have identified SSIH1 as the HAT responsible for the FZD10 dysregulation in SSs.