In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation.
In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation.
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DOI：
10.1016/j.cell.2017.10.025
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发表时间：
2017-12-14
期刊：
影响因子：
64.5
通讯作者：
Izpisua Belmonte JC
中科院分区：
文献类型：
--
作者：
Liao HK;Hatanaka F;Araoka T;Reddy P;Wu MZ;Sui Y;Yamauchi T;Sakurai M;O'Keefe DD;Núñez-Delicado E;Guillen P;Campistol JM;Wu CJ;Lu LF;Esteban CR;Izpisua Belmonte JC
目前的基因组编辑系统通常依赖于DNA双链断裂（DSB）的产生。这可能会限制它们在临床治疗中的效用，因为由DSB引起的不需要的突变可能具有有害影响。CRISPR/Cas9系统最近被重新利用，以实现靶基因激活，允许在不产生DSB的情况下调节内源性基因表达。然而，在体内实现这种功能增益系统已被证明是困难的。在这里，我们报告了一个强大的系统，在体内激活内源性靶基因通过trans-epigenetic重塑。该系统依赖于通过修饰的单向导RNA将Cas9和转录激活复合物募集到靶基因座。作为概念验证，我们使用这项技术来治疗几种人类疾病的小鼠模型。结果表明，CRISPR/Cas9介导的靶基因激活可以在体内实现，导致可观察到的表型变化和疾病症状的改善。这为开发针对人类疾病的靶向表观遗传疗法开辟了新途径。
Current genome-editing systems generally rely on the creation of DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. The CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat several mouse models of human diseases. Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to observable phenotypic changes, and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases.
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影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
48
作者：
Chavez A;Tuttle M;Pruitt BW;Ewen-Campen B;Chari R;Ter-Ovanesyan D;Haque SJ;Cecchi RJ;Kowal EJK;Buchthal J;Housden BE;Perrimon N;Collins JJ;Church G
通讯作者：
Church G
影响因子：
3.7
作者：
Janghra N;Morgan JE;Sewry CA;Wilson FX;Davies KE;Muntoni F;Tinsley J
通讯作者：
Tinsley J
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle
白细胞介素10缺乏会加重单侧输尿管梗阻小鼠模型的肾脏炎症和纤维化
影响因子：
5
作者：
Jin, Yuanmeng;Liu, Ruijie;Chen, Nan
通讯作者：
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