title: Telomeric transgenes are silenced in adult mouse tissues and embryo fibroblasts but are expressed in embryonic stem cells.
abstract: In addition to their role in protecting the ends of chromosomes, telomeres also influence the expression of adjacent genes, a process called telomere-position effect. We previously reported that the neo and HSV-tk transgenes located adjacent to telomeres in mouse embryonic stem cells are initially expressed at low levels and then become gradually silenced upon passage in culture through a process involving DNA methylation. We also reported extensive DNA methylation in these telomeric transgenes in three different tissues isolated from mice generated from one of these embryonic stem cell clones. In the present study, we demonstrate that embryo fibroblasts isolated from two different mouse strains show extensive DNA methylation and silencing of the telomeric transgenes. Consistent with this observation, we also demonstrate little or no detectable expression of the HSV-tk telomeric transgene in somatic tissues using whole body imaging. In contrast, both telomeric transgenes are expressed at low levels and have little DNA methylation in embryonic stem cell lines isolated from these same mouse strains. Our results demonstrate that telomere-position effect in mammalian cells can be observed either as a low level of expression in embryonic stem cells in the preimplantation embryo or as complete silencing and DNA methylation in differentiated cells and somatic tissues. This pattern of expression of the telomeric transgenes demonstrates that subtelomeric regions, like much of the genome, are epigenetically reprogrammed in the preimplantation embryo, a process that has been proposed to be important in early embryonic development. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Department of Radiation Oncology, University of California, 1855 Folsom Street, MCB 200, San Francisco, California 94103, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Reynolds
authors.forename: Lindsay
authors.initials: L
authors.lastname: Innes
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Pedram
authors.forename: Ella
authors.initials: E
authors.lastname: Jones
authors.forename: Mustafa
authors.initials: M
authors.lastname: Junabi
authors.forename: Dong-wei
authors.initials: DW
authors.lastname: Gao
authors.forename: Michelle
authors.initials: M
authors.lastname: Ricoul
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.forename: Henry
authors.initials: H
authors.lastname: Van Brocklin
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Franc
authors.forename: John P
authors.initials: JP
authors.lastname: Murnane
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics; D000818:Animals; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D016615:Telomere / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D014018:Tissue Distribution / Q000235:genetics; D019076:Transgenes