Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation.
Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation.
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DOI：
10.4161/epi.26267
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发表时间：
2013-11
期刊：
影响因子：
3.7
通讯作者：
Fedulov AV
中科院分区：
文献类型：
--
作者：
Gregory DJ;Zhang Y;Kobzik L;Fedulov AV
特异性地重新激活表观遗传沉默基因的能力将在实验研究和潜在的治疗价值中具有很大的效用。在这里，我们描述了胸苷dna糖基化酶（TDG），一种参与甲基胞嘧啶去甲基化机制的酶，特异性靶向Nos2启动子，一个在成纤维细胞中被甲基化沉默的基因，使用人工锌指DNA结合域。单个靶向TDG构建体对Nos2表达和甲基化的影响很小，但同时靶向四组TDG构建体可显著恢复对LPS和IFN刺激的反应性，并伴有启动子和CpG岛上显著的胞嘧啶去甲基化；不具有催化活性的TDG配合物没有影响。全基因组表达微阵列和通路分析发现，只有42个基因受到靶向TDG结构的影响；大多数可能在Nos2效应的下游。因此，这项研究表明，通过将去甲基酶靶向启动子，可以高度特异性、定向地重新激活单个沉默基因。
The ability to specifically reactivate epigenetically silenced genes would have great utility in experimental studies and potential therapeutic value. Here, we describe the specific targeting of thymidine DNA glycosylase (TDG), an enzyme involved in the mechanism of methylcytosine demethylation, to the promoter of Nos2, a gene silenced by methylation in fibroblasts, using artificial zinc finger DNA binding domains. Individual targeted TDG constructs had a small effect on Nos2 expression and methylation, but simultaneous targeting of a quartet of TDG constructs significantly restored responsiveness to LPS and IFN stimuli in association with marked cytosine demethylation at the promoter and CpG island; catalytically inactive TDG complexes had no effect. Whole-genome expression microarray and pathway analysis found only 42 genes that were affected by targeted TDG constructs; the majority are likely downstream of the effect on Nos2. This study therefore shows highly specific, directed reactivation of a single, silenced gene by targeting of a demethylase to the promoter.
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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：
Rivenbark, Ashley G.;Stolzenburg, Sabine;Blancafort, Pilar
通讯作者：
Blancafort, Pilar
DOI：
10.1073/pnas.091097298
发表时间：
2001-04-24
影响因子：
11.1
作者：
Zhu, B;Benjamin, D;Jost, JP
通讯作者：
Jost, JP
影响因子：
48
作者：
Gaj, Thomas;Guo, Jing;Kato, Yoshio;Sirk, Shannon J.;Barbas, Carlos F., III
通讯作者：
Barbas, Carlos F., III
影响因子：
4.7
作者：
Majid, Shahana;Dar, Altaf A.;Dahiya, Rajvir
通讯作者：
Dahiya, Rajvir