Induced DNA demethylation by targeting Ten-Eleven Translocation 2 to the human ICAM-1 promoter.
Induced DNA demethylation by targeting Ten-Eleven Translocation 2 to the human ICAM-1 promoter.
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DOI：
10.1093/nar/gkt1019
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发表时间：
2014-02
影响因子：
14.9
通讯作者：
Rots MG
中科院分区：
文献类型：
--
作者：
Chen H;Kazemier HG;de Groote ML;Ruiters MH;Xu GL;Rots MG
越来越多的证据表明，主动DNA去甲基化参与了哺乳动物的几个过程，导致发育阶段特异性和细胞谱系特异性。最近发现的10 - 11易位（泰特）双加氧酶被认为通过启动5-mC氧化而参与DNA去甲基化。异常的DNA甲基化谱与许多疾病有关。例如在癌症中，超甲基化导致肿瘤抑制基因沉默。这种沉默的基因可以通过表观遗传药物重新表达，但这种方法具有全基因组效应。在这项研究中，设计者DNA结合结构域与泰特双加氧酶家族成员（TET 1、TET-2或TET-3）的融合物被工程化以靶向表观遗传学沉默的基因（ICAM-1、EpCAM）。评估了对靶向CpG甲基化和靶基因表达水平的影响。结果表明，对于靶向TET 2和TET 1，两种启动子中的靶向CpG位点的去甲基化程度较低，但对于TET 3则没有。有趣的是，我们观察到ICAM-1转录的重新激活。因此，我们的工作表明，我们提供了一种诱导靶向DNA去甲基化的机制，这有助于靶基因表达的重新激活。此外，这种表观遗传编辑方法是研究表观遗传书写器和擦除器的功能以及阐明表观遗传标记的后果的有力工具。
Increasing evidence indicates that active DNA demethylation is involved in several processes in mammals, resulting in developmental stage-specificity and cell lineage-specificity. The recently discovered Ten-Eleven Translocation (TET) dioxygenases are accepted to be involved in DNA demethylation by initiating 5-mC oxidation. Aberrant DNA methylation profiles are associated with many diseases. For example in cancer, hypermethylation results in silencing of tumor suppressor genes. Such silenced genes can be re-expressed by epigenetic drugs, but this approach has genome-wide effects. In this study, fusions of designer DNA binding domains to TET dioxygenase family members (TET1, -2 or -3) were engineered to target epigenetically silenced genes (ICAM-1, EpCAM). The effects on targeted CpGs’ methylation and on expression levels of the target genes were assessed. The results indicated demethylation of targeted CpG sites in both promoters for targeted TET2 and to a lesser extent for TET1, but not for TET3. Interestingly, we observed re-activation of transcription of ICAM-1. Thus, our work suggests that we provided a mechanism to induce targeted DNA demethylation, which facilitates re-activation of expression of the target genes. Furthermore, this Epigenetic Editing approach is a powerful tool to investigate functions of epigenetic writers and erasers and to elucidate consequences of epigenetic marks.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
3.7
作者：
Gregory, David J.;Mikhaylova, Lyudmila;Fedulov, Alexey V.
通讯作者：
Fedulov, Alexey V.
影响因子：
3.7
作者：
Globisch D;Münzel M;Müller M;Michalakis S;Wagner M;Koch S;Brückl T;Biel M;Carell T
通讯作者：
Carell T
影响因子：
6.4
作者：
de Groote, Marloes L.;Kazemier, Hinke G.;Rots, Marianne G.
通讯作者：
Rots, Marianne G.
影响因子：
64.5
作者：
Guo JU;Su Y;Zhong C;Ming GL;Song H
通讯作者：
Song H