Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 7, Pages 3135-3140Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914142107
Keywords
chromatin; histone marks; lentiviral vectors
Categories
Funding
- National Institutes of Health (NIH) (National Cancer Institute) [AI039394, T32 AI007386, GM53122]
- Rockefeller University
- Emerald Foundation
- [HHSN261200800001E]
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Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1 alpha (HP1 alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1 alpha chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1 alpha chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy.
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