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Molecular and Cellular Biology, April 2006, p. 2583-2594, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2583-2594.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role for Centromeric Heterochromatin and PML Nuclear Bodies in the Cellular Response to Foreign DNA

Cleo L. Bishop,¹ Michal Ramalho,^1, Nachiket Nadkarni,¹ Wing May Kong,^2, Christopher F. Higgins,¹ and Nina Krauzewicz^1*

MRC Clinical Sciences Centre,¹ Department of Metabolic Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom²

Received 7 September 2005/ Returned for modification 11 November 2005/ Accepted 11 January 2006

Nuclear spatial positioning plays an important role in the epigenetic regulation of eukaryotic gene expression. Here we show a role for nuclear spatial positioning in regulating episomal transgenes that are delivered by virus-like particles (VLPs). VLPs mediate the delivery of plasmid DNA (pDNA) to cell nuclei but lack viral factors involved in initiating and regulating transcription. By tracking single fluorescently labeled VLPs, coupled with luciferase reporter gene assays, we found that VLPs transported pDNA to cell nuclei efficiently but transgenes were immediately silenced by the cell. An investigation of the nuclear location of fluorescent VLPs revealed that the pDNAs were positioned next to centromeric heterochromatin. The activation of transcription by providing viral factors or inhibiting histone deacetylase activity resulted in the localization to euchromatin regions. Further, the activation of transcription induced the recruitment of PML nuclear bodies (PML-NBs) to the VLPs. This association did not play a role in regulating transgene expression, but PML protein was necessary for the inhibition of transgene expression with alpha interferon (IFN-). These results support a model whereby cells can prevent foreign gene expression at two levels: by positioning transgenes next to centromeric heterochromatin or, if that is overcome, via the type I IFN response facilitated by PML-NB recruitment.

Present address: Department of Cancer Genetics, Division of Genetics and Molecular Medicine, Guy's Hospital, London SE1 9RT, United Kingdom.

Present address: Centre for Research on Drugs and Health Behaviour, Imperial College London, Charing Cross Campus, St. Dunstan's Road, London W6 8RP, United Kingdom.

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