Instituto de Fisiología Celular, Departamento de Genética Molecular, Universidad Nacional Autónoma de México, México D.F., México.
Oncogene. 2010 Apr 15;29(15):2217-27. doi: 10.1038/onc.2009.509. Epub 2010 Jan 25.
Epigenetic silencing of tumor suppressor gene promoters has become a more frequent phenomenon in cancer than previously anticipated. In this study we addressed the mechanisms involved in the protection of the p53 tumor suppressor gene against epigenetic silencing in human transformed cell lines. We characterized a binding site for the CCCTC-binding factor (CTCF) in the human p53 gene promoter that contributes to its transcriptional expression, and has the ability to maintain this regulatory element in a local open chromatin configuration. In the absence of CTCF we observe the incorporation of repressive histone marks, such as H3K9me3, H3K27me3 and H4K20me3, in different sub-domains of the upstream regulatory sequence. This evidence suggests that CTCF protects the p53 gene promoter against repressive histone marks. Notably, no apparent direct correlation between repression and DNA hypermethylation has been detected. Together, we present evidence supporting the relevant role of CTCF in the epigenetic regulation of tumor suppressor genes and cancer. We propose that CTCF is a strategic component responsible for the maintenance and segregation of epigenetic traits.
肿瘤抑制基因启动子的表观遗传沉默在癌症中比以前预期的更为常见。在这项研究中，我们研究了参与人转化细胞系中 p53 肿瘤抑制基因免受表观遗传沉默的保护机制。我们鉴定了人 p53 基因启动子中一个结合 CCCTC 结合因子（CTCF）的结合位点，该结合位点有助于其转录表达，并具有将该调控元件维持在局部开放染色质构象的能力。在缺乏 CTCF 的情况下，我们观察到不同的上游调控序列亚区中存在抑制性组蛋白标记，如 H3K9me3、H3K27me3 和 H4K20me3。这一证据表明 CTCF 保护 p53 基因启动子免受抑制性组蛋白标记的影响。值得注意的是，没有检测到抑制作用与 DNA 超甲基化之间存在明显的直接相关性。综上所述，我们提供的证据支持 CTCF 在肿瘤抑制基因和癌症的表观遗传调控中的重要作用。我们提出 CTCF 是负责维持和分离表观遗传特征的关键组成部分。
