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Impact of cell division on the distribution of HIV integration.

ABSTRACT: DNA integration is a defining step in the retroviral life cycle and the basis of stable gene transfer in retrovirus-based gene therapy. Previous studies of integration by HIV-based vectors have shown that integration is not random, but favored in active transcription units. Studies to date have focused on HIV integration in dividing cells, leaving open the question of whether integration target site selection might differ in nondividing cells. According to one idea, division of the host cell might be required for favored integration in transcription units, possibly as a result of chromatin remodeling during DNA replication. Here we have investigated this issue by comparing integration in dividing IMR-90 primary lung fibroblasts to integration in nondividing IMR-90 cells arrested in G1 by serum starvation and contact inhibition. We identified several differences in integration site selection in arrested versus dividing cells, including the frequency of integration in transcription units and in gene-rich regions. However, integration in nondividing cells was in fact more favored in transcription units, contrary to the idea that cell division was important for this bias. These data provide the first view of lentiviral integration in nondividing cells and help constrain models for the mechanism of favored integration in genes. Keywords: comparative genomic analysis, dividing versus non-dividing cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE3555 | GEO | 2005/11/10

SECONDARY ACCESSION(S): PRJNA93631

REPOSITORIES: GEO

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Transcription profiling of human IMR-90 cells passaged 36 times to investigate the impact of cell division on the distribution of HIV integration.

Project description:DNA integration is a defining step in the retroviral life cycle and the basis of stable gene transfer in retrovirus-based gene therapy. Previous studies of integration by HIV-based vectors have shown that integration is not random, but favored in active transcription units. Studies to date have focused on HIV integration in dividing cells, leaving open the question of whether integration target site selection might differ in nondividing cells. According to one idea, division of the host cell might be required for favored integration in transcription units, possibly as a result of chromatin remodeling during DNA replication. Here we have investigated this issue by comparing integration in dividing IMR-90 primary lung fibroblasts to integration in nondividing IMR-90 cells arrested in G1 by serum starvation and contact inhibition. We identified several differences in integration site selection in arrested versus dividing cells, including the frequency of integration in transcription units and in gene-rich regions. However, integration in nondividing cells was in fact more favored in transcription units, contrary to the idea that cell division was important for this bias. These data provide the first view of lentiviral integration in nondividing cells and help constrain models for the mechanism of favored integration in genes. Experiment Overall Design: IMR-90 cells (initially passaged 36 times) were cultured in DMEM with 10% FBS until the cells reached 100% confluence, at which point the medium was substituted to contain only 0.5% FBS. The cells were cultivated for 2 weeks prior to harvesting for RNA extraction. 2 arrays were hybridized, using RNA from 2 independent cell cultures. The data of these growth arrested cells was compared to dividing IMR90 cells (Mitchell et al. 2004. PLoS Biology. 2(8):E234).

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