Genomic discovery of potent chromatin insulators for human gene therapy

A genome-wide analysis of CTCF binding sites yields compact sequence elements that function as chromatin insulators. Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator seq...

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Bibliographic Details
Published in:Nature biotechnology 2015-02, Vol.33 (2), p.198-203
Main Authors: Liu, Mingdong, Maurano, Matthew T, Wang, Hao, Qi, Heyuan, Song, Chao-Zhong, Navas, Patrick A, Emery, David W, Stamatoyannopoulos, John A, Stamatoyannopoulos, George
Format: Article
Language:English
Subjects:
631/114/2397
631/1647/2300/1514
631/208/200
631/61/201
Agriculture
Animal models
Binding Sites - genetics
Bioinformatics
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
CCCTC-Binding Factor
Chromatin
Chromatin - genetics
Computational Biology
Enhancer Elements, Genetic
Gene Expression Regulation
Gene therapy
Genetic disorders
Genetic research
Genetic Therapy
Genetic Vectors
Genome, Human
Genomics
Genotoxicity
Health aspects
Humans
Identification and classification
Insulator Elements - genetics
Life Sciences
Methods
Mutagenesis
Nucleotide sequence
Repressor Proteins - genetics
Repressor Proteins - metabolism
Sequence Analysis, DNA
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Description
Summary:A genome-wide analysis of CTCF binding sites yields compact sequence elements that function as chromatin insulators. 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.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.3062