Position effect variegation and imprinting of transgenes in lymphocytes

Sequences proximal to transgene integration sites are able to deregulate transgene expression resulting in complex position effect phenotypes. In addition, transgenes integrated as repeated arrays are susceptible to repeat-induced gene silencing. Using a Cre recombinase-based system we have addresse...

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Bibliographic Details
Published in:Nucleic acids research 2008-04, Vol.36 (7), p.2320-2329
Main Authors: Williams, Adam, Harker, Nicola, Ktistaki, Eleni, Veiga-Fernandes, Henrique, Roderick, Kathleen, Tolaini, Mauro, Norton, Trisha, Williams, Keith, Kioussis, Dimitris
Format: Article
Language:English
Subjects:
Animals
CD2 Antigens - genetics
CD2 Antigens - metabolism
Chromatin Immunoprecipitation
DNA Methylation
Flow Cytometry
Gene Dosage
Gene Silencing
Genomic Imprinting
Humans
Locus Control Region
Mice
Mice, Transgenic
Molecular Biology
T-Lymphocytes - immunology
Transgenes
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Description
Summary:Sequences proximal to transgene integration sites are able to deregulate transgene expression resulting in complex position effect phenotypes. In addition, transgenes integrated as repeated arrays are susceptible to repeat-induced gene silencing. Using a Cre recombinase-based system we have addressed the influence of transgene copy number (CN) on expression of hCD2 transgenes. CN reduction resulted in a decrease, increase or no effect on variegation depending upon the site of integration. This finding argues that repeat-induced gene silencing is not the principle cause of hCD2 transgene variegation. These results also suggest that having more transgene copies can be beneficial at some integration sites. The transgenic lines examined in this report also exhibited a form of imprinting, which was manifested by decreased levels of expression and increased levels of variegation, upon maternal transmission; and this correlated with DNA hypermethylation and a reduction in epigenetic chromatin modifications normally associated with active genes.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkn085