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Transcription-dependent silencing of inducible convergent transgenes in transgenic mice

Calero-Nieto, F.J., Bert, A.G. and Cockerill, P.N. (2010) Transcription-dependent silencing of inducible convergent transgenes in transgenic mice. Epigenetics & Chromatin , 3.

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Abstract

BACKGROUND Silencing of transgenes in mice is a common phenomenon typically associated with short multi-copy transgenes. We have investigated the regulation of the highly inducible human granulocyte-macrophage colony-stimulating-factor gene (Csf2) in transgenic mice.

RESULTS In the absence of any previous history of transcriptional activation, this transgene was expressed in T lineage cells at the correct inducible level in all lines of mice tested. In contrast, the transgene was silenced in a specific subset of lines in T cells that had encountered a previous episode of activation. Transgene silencing appeared to be both transcription-dependent and mediated by epigenetic mechanisms. Silencing was accompanied by loss of DNase I hypersensitive sites and inability to recruit RNA polymerase II upon stimulation. This pattern of silencing was reflected by increased methylation and decreased acetylation of histone H3 K9 in the transgene. We found that silenced lines were specifically associated with a single pair of tail-to-tail inverted repeated copies of the transgene embedded within a multi-copy array.

CONCLUSIONS Our study suggests that epigenetic transgene silencing can result from convergent transcription of inverted repeats which can lead to silencing of an entire multi-copy transgene array. This mechanism may account for a significant proportion of the reported cases of transgene inactivation in mice.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Calero-Nieto et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 06 May 2010 11:25
Last Modified: 29 Sep 2010 14:25
Published Version: http://dx.doi.org/10.1186/1756-8935-3-3
Status: Published
Publisher: Biomed Central
Refereed: Yes
Identification Number: 10.1186/1756-8935-3-3
Related URLs:
URI: http://eprints.whiterose.ac.uk/id/eprint/10799

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