De La Rosa-Velázquez Inti A, Rincón-Arano Héctor, Benítez-Bribiesca Luis, Recillas-Targa Félix
Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, México D.F., México.
Cancer Res. 2007 Mar 15;67(6):2577-85. doi: 10.1158/0008-5472.CAN-06-2024.
Epigenetic misregulation is a more common feature in human cancer than previously anticipated. In the present investigation, we identified CCCTC-binding factor (CTCF), the multivalent 11-zinc-finger nuclear factor, as a regulator that favors a particular local chromatin conformation of the human retinoblastoma gene promoter. We show that its binding contributes to Rb gene promoter epigenetic stability. Ablation of the CTCF binding site from the human Rb gene promoter induced a rapid epigenetic silencing of reporter gene expression in an integrated genome context. CTCF DNA binding is methylation sensitive, and the methylated Rb-CTCF site is recognized by the Kaiso methyl-CpG-binding protein. This is the first evidence suggesting that CTCF protects the Rb gene promoter, a classic CpG island, against DNA methylation, and when such control region is abnormally methylated Kaiso, and probably its associated repressor complex, induce epigenetic silencing of the promoter. Our results identify CTCF as a novel epigenetic regulator of the human retinoblastoma gene promoter.
表观遗传失调在人类癌症中是一个比先前预期更为常见的特征。在本研究中，我们鉴定出CCCTC结合因子（CTCF），一种具有多价性的11锌指核因子，作为一种有利于人视网膜母细胞瘤基因启动子特定局部染色质构象的调节因子。我们表明其结合有助于Rb基因启动子的表观遗传稳定性。从人Rb基因启动子中去除CTCF结合位点会在整合基因组背景下诱导报告基因表达的快速表观遗传沉默。CTCF与DNA的结合对甲基化敏感，并且甲基化的Rb-CTCF位点可被Kaiso甲基化CpG结合蛋白识别。这是首个表明CTCF保护Rb基因启动子（一个经典的CpG岛）免受DNA甲基化影响的证据，并且当这样的调控区域异常甲基化时，Kaiso以及可能其相关的阻遏复合物会诱导启动子的表观遗传沉默。我们的结果将CTCF鉴定为人视网膜母细胞瘤基因启动子的一种新型表观遗传调节因子。
