This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pedram, M. Articles by Murnane, J. P. Search for Related Content PubMed PubMed Citation Articles by Pedram, M. Articles by Murnane, J. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

 Previous Article  |  Next Article 

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.

---

* Corresponding author. Mailing address: Department of Radiation Oncology, University of California, 1855 Folsom St., MCB 200, San Francisco, CA 94103. Phone: (415) 476-9083. Fax: (415) 476-9069. E-mail: murnane{at}radonc17.ucsf.edu.

^¶ 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.

---

Molecular and Cellular Biology, March 2006, p. 1865-1878, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1865-1878.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Maeda, T., Guan, J. Z., Oyama, J.-i., Higuchi, Y., Makino, N. (2009). Aging-Associated Alteration of Subtelomeric Methylation in Parkinson's Disease. J Gerontol A Biol Sci Med Sci 64A: 949-955 [Abstract] [Full Text]  
• Esnault, G., Majocchi, S., Martinet, D., Besuchet-Schmutz, N., Beckmann, J. S., Mermod, N. (2009). Transcription Factor CTF1 Acts as a Chromatin Domain Boundary That Shields Human Telomeric Genes from Silencing. Mol. Cell. Biol. 29: 2409-2418 [Abstract] [Full Text]  
• Maeda, T., Guan, J. Z., Oyama, J.-i., Higuchi, Y., Makino, N. (2009). Age-Related Changes in Subtelomeric Methylation in the Normal Japanese Population. J Gerontol A Biol Sci Med Sci 64A: 426-434 [Abstract] [Full Text]  
• Verras, M., Papandreou, I., Lim, A. L., Denko, N. C. (2008). Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum Stress. Mol. Cell. Biol. 28: 7212-7224 [Abstract] [Full Text]  
• Oh, R., Ho, R., Mar, L., Gertsenstein, M., Paderova, J., Hsien, J., Squire, J. A., Higgins, M. J., Nagy, A., Lefebvre, L. (2008). Epigenetic and Phenotypic Consequences of a Truncation Disrupting the Imprinted Domain on Distal Mouse Chromosome 7. Mol. Cell. Biol. 28: 1092-1103 [Abstract] [Full Text]  
• Rincon-Arano, H., Furlan-Magaril, M., Recillas-Targa, F. (2007). Protection against telomeric position effects by the chicken cHS4 beta-globin insulator. Proc. Natl. Acad. Sci. USA 104: 14044-14049 [Abstract] [Full Text]  
• Maser, R. S., Wong, K.-K., Sahin, E., Xia, H., Naylor, M., Hedberg, H. M., Artandi, S. E., DePinho, R. A. (2007). DNA-Dependent Protein Kinase Catalytic Subunit Is Not Required for Dysfunctional Telomere Fusion and Checkpoint Response in the Telomerase-Deficient Mouse. Mol. Cell. Biol. 27: 2253-2265 [Abstract] [Full Text]  
• Pawlitzky, I., Angeles, C. V., Siegel, A. M., Stanton, M. L., Riblet, R., Brodeur, P. H. (2006). Identification of a Candidate Regulatory Element within the 5' Flanking Region of the Mouse Igh Locus Defined by Pro-B Cell-Specific Hypersensitivity Associated with Binding of PU.1, Pax5, and E2A.. J. Immunol. 176: 6839-6851 [Abstract] [Full Text]