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Safe harbours for the integration of new DNA in the human genome

Abstract

Interactions between newly integrate DNA and the host genome limit the reliability and safety of transgene integration for therapeutic cell engineering and other applications. Although targeted gene delivery has made considerable progress, the question of where to insert foreign sequences in the human genome to maximize safety and efficacy has received little attention. In this Opinion article, we discuss 'genomic safe harbours' — chromosomal locations where therapeutic transgenes can integrate and function in a predictable manner without perturbing endogenous gene activity and promoting cancer.

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Figure 1: Intragenic candidate GSHs.
Figure 2: Prospective extragenic GSHs in human iPS cell clones harbouring single-copy globin transgenes.

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Acknowledgements

The authors thank N. Malani, S. Roth and A. Bailey for help with the Cancer Gene database. This work was supported by US NIH grants CA059350, HL053750, DK087923, AI052845 and AI082020 and by the New York State Stem Cell Science (NYSTEM) grant N08T060.

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Correspondence to Michel Sadelain.

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FURTHER INFORMATION

Michel Sadelain's homepage

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cancer Gene Census

Retroviral Tagged Cancer Gene Database (RTCGD)

The Bushman lab cancer gene list

Waldman gene database

Glossary

Euchromatic portion

A region of chromatin that has lighter packing than heterochromatin and that is generally considered to be richer in actively transcribed genes.

Gene trapping screen

A high-throughput approach used to report and/or inactivate the expression of multiple individual genes across the genome by introducing a reporter gene lacking a promoter (through plasmid or retroviral gene transfer). Selection for expression of the gene requires transcription from a cellular promoter.

Insulator elements

Regulatory DNA elements that create boundaries in chromatin, delineating the ranges over which neighbouring regulatory elements function. They can have enhancer-blocking activity, which prevents communication between discrete sequence elements (typically enhancers and promoters) when insulators are positioned between them, and/or barrier activity, which prevents the spread of heterochromatin.

Intergenic transcription

Transcription of chromosomal DNA sequences between known genes.

Locus control regions

A class of cis-acting DNA regulatory elements that confer high level, tissue-specific, site-of-integration-independent, copy number-dependent expression on linked transgenes located at ectopic chromatin sites.

Matrix attachment regions

AT-rich sequences of DNA that bind to a proteinaceous nuclear scaffold called the nuclear matrix.

Meganucleases

Sequence-specific endonucleases with long recognition sites (>12bp). They are naturally occurring enzymes that are harnessed as tools for targeted genome engineering by the modification of their recognition sequence.

Proviruses

The duplex DNA form of the retroviral genome linked to a cellular chromosome. The provirus is produced by reverse transcription of the RNA genome and subsequent integration into the chromosomal DNA of the host cell.

Retroviral pre-integration complexes

Complexes of viral and cellular proteins with retroviral DNA made by reverse transcription, which together are capable of integrating the viral DNA into a target DNA.

Sub-telomeric regions

Regions adjacent to the telomeres or tips of chromosomes that are often heterochromatic.

Transcription activator-like effector (TALE) nucleases

Artificial endonucleases generated by fusing a TALE DNA-binding domain to the catalytic domain of an endonuclease that introduces double-strand breaks. Similar to zinc-finger nucleases and meganucleases, TALE nucleases can also be engineered to target user-specified DNA sequences within complex genomes.

Zinc-finger nucleases

A class of synthetic proteins that are generated by fusing a zinc-finger DNA-binding domain to the cleavage domain of the FokI restriction endonuclease. The DNA-binding domain can be engineered to induce double-strand breaks in desired DNA sequences, thus facilitating site-specific homologous recombination by the endogenous DNA repair machinery and targeted editing of a genomic locus (insertion, deletion and single-base substitution).

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Sadelain, M., Papapetrou, E. & Bushman, F. Safe harbours for the integration of new DNA in the human genome. Nat Rev Cancer 12, 51–58 (2012). https://doi.org/10.1038/nrc3179

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