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Molecular and Cellular Biology, March 2006, p. 1865-1878, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1865-1878.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Telomere Position Effect and Silencing of Transgenes near Telomeres in the Mouse^¶

Mehrdad Pedram, Carl N. Sprung, Qing Gao, Anthony W. I. Lo, Gloria E. Reynolds, and John P. Murnane^*

Department of Radiation Oncology, University of California, San Francisco, 1855 Folsom St., MCB 200, San Francisco, California 94103

Received 28 June 2005/ Returned for modification 29 July 2005/ Accepted 6 December 2005

Reversible transcriptional silencing of genes located near telomeres, termed the telomere position effect (TPE), is well characterized in Saccharomyces cerevisiae. TPE has also been observed in human tumor cell lines, but its function remains unknown. To investigate TPE in normal mammalian cells, we developed clones of mouse embryonic stem (ES) cells that contain single-copy marker genes integrated adjacent to different telomeres. Analysis of these telomeric transgenes demonstrated that they were expressed at very low levels compared to the same transgenes integrated at interstitial sites. Similar to the situation in yeast, but in contrast to studies with human tumor cell lines, TPE in mouse ES cells was not reversed with trichostatin A. Prolonged culturing without selection resulted in extensive DNA methylation and complete silencing of telomeric transgenes, which could be reversed by treatment with 5-azacytidine. Thus, complete silencing of the telomeric transgenes appears to involve a two-step process in which the initial repression is reinforced by DNA methylation. Extensive methylation of the telomeric transgenes was also observed in various tissues and embryonic fibroblasts isolated from transgenic mice. In contrast, telomeric transgenes were not silenced in ES cell lines isolated from 3-day-old preimplantation embryos, consistent with the hypothesis that TPE plays a role in the development of the embryo.

^¶ Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.

Present address: Divisions of Research, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.

Present address: Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.

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