Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy.
Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy.
复制标题
DOI：
10.18632/oncotarget.3272
复制
发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Hahn H
中科院分区：
文献类型：
--
作者：
Nitzki F;Tolosa EJ;Cuvelier N;Frommhold A;Salinas-Riester G;Johnsen SA;Fernandez-Zapico ME;Hahn H
肿瘤抑制基因Patched 1（Ptch）杂合缺失的小鼠会发生横纹肌肉瘤（RMS）样肿瘤。然而，Ptch转录物在这些肿瘤中始终过表达。我们最近表明，上调的成绩单来自突变Ptch等位基因，从而导致的假设，即野生型等位基因在RMS发展过程中受到抑制。在这里，我们描述发生在Ptch位点RMS发展过程中的表观遗传变化。我们发现RMS中Ptch启动子甲基化敏感CpG区域的DNA甲基化程度低于杂合Ptch动物的正常肌肉。与这些结果一致，在胚胎期E9.5-E11.5之间用DNA去甲基化剂5-氮杂-2-脱氧胞苷（5-aza-dC）处理杂合Ptch小鼠显著加速RMS形成。由于Ptch启动子甲基化发生在E13.5（胚胎发生期间RMS起始的窗口）之后/附近，因此这些结果提供了Ptch启动子低甲基化可能有助于RMS形成的额外证据。我们还证明了组蛋白H3赖氨酸4（H3 K4 me 3）的三甲基化增加和Gli 1（一种已知的Ptch激活剂）与RMS突变位点的优先结合。总之，这些发现支持杂合Ptch小鼠中RMS形成的替代模型，包括甲基化的丧失和通过激活突变Ptch的组蛋白标记的伴随占据。
Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5–E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch.
登录
查看更多内容
影响因子：
5.7
作者：
Delcuve GP;Khan DH;Davie JR
通讯作者：
Davie JR
影响因子：
11.5
作者：
Evangelista, Marie;Tian, Hua;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
人胰腺癌中 DNMT1 和 DNMT3a 的表达受 GLI1 调节。
影响因子：
3.7
作者：
He S;Wang F;Yang L;Guo C;Wan R;Ke A;Xu L;Hu G;Xu X;Shen J;Wang X
通讯作者：
Wang X
影响因子：
12.3
作者：
Balasubramanian D;Akhtar-Zaidi B;Song L;Bartels CF;Veigl M;Beard L;Myeroff L;Guda K;Lutterbaugh J;Willis J;Crawford GE;Markowitz SD;Scacheri PC
通讯作者：
Scacheri PC
影响因子：
4.4
作者：
Hahn, H;Nitzki, F;Rosemann, M
通讯作者：
Rosemann, M