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Designer epigenome modifiers enable robust and sustained gene silencing in clinically relevant human cells
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2018-03-10 , DOI: 10.1093/nar/gky171
Tafadzwa Mlambo 1, 2, 3, 4 , Sandra Nitsch 1, 2, 4 , Markus Hildenbeutel 1, 2 , Marianna Romito 1, 2, 4 , Maximilian Müller 1, 2, 4 , Claudia Bossen 2 , Sven Diederichs 5, 6 , Tatjana I Cornu 1, 2 , Toni Cathomen 1, 2, 6 , Claudio Mussolino 1, 2
Affiliation  

Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkably high specificity, paving the way for the establishment of a potential new class of therapeutics.

中文翻译:

设计师的表观基因组修饰剂可在临床相关的人类细胞中实现强大而持久的基因沉默

基因表达的靶向调节代表了一种了解调控基因调控机制的有价值的方法。在治疗方面,可以利用它来选择性修饰致病基因的异常表达或为靶细胞提供新功能。在这里,我们建立了一个新颖的平台,可使用设计器表观基因组修饰符(DEM)实现精确的表观基因组编辑。DEM在单个分子中结合了基于高度特异性转录激活因子样效应物(TALE)的DNA结合域和几个能够诱导DNA甲基化并局部改变染色质结构以沉默靶基因表达的效应域。我们设计了针对两种人类基因CEM5CXCR4的DEM,目的是通过表观遗传沉默它们在原代人T淋巴细胞中的表达。我们观察到与染色质可及性降低,目标位点启动子甲基化增加以及全局基因表达无法检测到的变化相关的强大且持续的靶基因沉默。我们的结果表明,DEM可以成功地用于沉默具有显着高特异性的原代人类细胞中的靶基因表达,从而为建立潜在的新型疗法铺平了道路。
更新日期:2018-03-10
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