Target Site Preferences of Subgroup C Rous Sarcoma Virus Integration into the Chicken DNA

Reinišová, Markéta; Pavlı́ček, Adam; Divina, Petr; Geryk, Josef; Plachý, Jiřı́; Hejnar, Jiřı́

doi:10.2174/1875693x00801010006

Cited by 2 publications

(3 citation statements)

References 38 publications

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“…MLV also integrates with a high preference for expressed genes, particularly into the transcriptional start sites of genes (51), and such integration might transcriptionally activate adjacent proto-oncogenes, as shown in the SCID-X1 gene therapy trial (17). In comparison with MLV and HIV-1, ASLVs display the weakest preference for integration into genes and have no bias for promoter regions (35,38,42). Hence, ASLVbased vectors might be safer than the widely used lentiviral or MLV-based vectors.…”

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confidence: 99%

The Core Element of a CpG Island Protects Avian Sarcoma and Leukosis Virus-Derived Vectors from Transcriptional Silencing

Šenigl

Plachý

Hejnar

2008

J Virol

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Unmethylated CpG islands are known to keep adjacent promoters transcriptionally active. In the CpG island adjacent to the adenosine phosphoribosyltransferase gene, the protection against transcriptional silencing can be attributed to the short CpG-rich core element containing Sp1 binding sites. We report here the insertion of this CpG island core element, IE, into the long terminal repeat of a retroviral vector derived from Rous sarcoma virus, which normally suffers from progressive transcriptional silencing in mammalian cells. IE insertion into a specific position between enhancer and promoter sequences led to efficient protection of the integrated vector from silencing and gradual CpG methylation in rodent and human cells. Individual cell clones with IE-modified reporter vectors display high levels of reporter expression for a sustained period and without substantial variegation in the cell culture. The presence of Sp1 binding sites is important for the protective effect of IE, but at least some part of the entire antisilencing capacity is maintained in IE with mutated Sp1 sites. We suggest that this strategy of antisilencing protection by the CpG island core element may prove generally useful in retroviral vectors.

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confidence: 99%

The Core Element of a CpG Island Protects Avian Sarcoma and Leukosis Virus-Derived Vectors from Transcriptional Silencing

Šenigl

Plachý

Hejnar

2008

J Virol

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“…Amplification and cloning of sequences flanking the 5Ј long terminal repeat (LTR) of pH19KE proviruses were done as described by Reinišová et al (38) with slight modifications (Fig. 2).…”

Section: Methodsmentioning

confidence: 99%

“…This approach has been rapidly applied to a wide variety of retroviruses, and several comparative studies have shown surprising differences between their integration preferences. While HIV-1 preferentially targets genes, particularly the transcriptionally active ones (10,42,33), avian sarcoma and leukosis viruses (ASLVs) integrate with only slight preference for genes (1,33,34,38). The most random dispersion of integration without any tendency to integrate within genes was observed for mouse mammary tumor virus (12).…”

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confidence: 99%

Proviruses Selected for High and Stable Expression of Transduced Genes Accumulate in Broadly Transcribed Genome Areas

Plachý

Kotáb

Divina

et al. 2010

J Virol

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Retroviruses and retrovirus-derived vectors integrate nonrandomly into the genomes of host cells with specific preferences for transcribed genes, gene-rich regions, and CpG islands. However, the genomic features that influence the transcriptional activities of integrated retroviruses or retroviral vectors are poorly understood. We report here the cloning and characterization of avian sarcoma virus integration sites from chicken tumors. Growing progressively, dependent on high and stable expression of the transduced v-src oncogene, these tumors represent clonal expansions of cells bearing transcriptionally active replication-defective proviruses. Therefore, integration sites in our study distinguished genomic loci favorable for the expression of integrated retroviruses and gene transfer vectors. Analysis of integration sites from avian sarcoma virusinduced tumors showed strikingly nonrandom distribution, with proviruses found prevalently within or close to transcription units, particularly in genes broadly expressed in multiple tissues but not in tissue-specifically expressed genes. We infer that proviruses integrated in these genomic areas efficiently avoid transcriptional silencing and remain active for a long time during the growth of tumors. Defining the differences between unselected retroviral integration sites and sites selected for long-terminal-repeat-driven gene expression is relevant for retrovirus-mediated gene transfer and has ramifications for gene therapy.

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Target Site Preferences of Subgroup C Rous Sarcoma Virus Integration into the Chicken DNA

Cited by 2 publications

References 38 publications

The Core Element of a CpG Island Protects Avian Sarcoma and Leukosis Virus-Derived Vectors from Transcriptional Silencing

The Core Element of a CpG Island Protects Avian Sarcoma and Leukosis Virus-Derived Vectors from Transcriptional Silencing

Proviruses Selected for High and Stable Expression of Transduced Genes Accumulate in Broadly Transcribed Genome Areas

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