期刊
NATURE BIOTECHNOLOGY
卷 33, 期 2, 页码 198-203出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3062
关键词
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资金
- US National Institutes of Health (NIH) [PO1 HL53750, R90 HG004152]
- [U54 HG007010]
- [UO1 ES017156]
- [F31 MH 094073]
Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified: Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases.
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