title: Telomerase reverse transcriptase has an extratelomeric function in somatic cell reprogramming.
abstract: Reactivation of the endogenous telomerase reverse transcriptase (TERT) catalytic subunit and telomere elongation occur during the reprogramming of somatic cells to induced pluripotent stem (iPS) cells. However, the role of TERT in the reprogramming process is unclear. To clarify its function, the reprogramming process was examined in TERT-KO somatic cells. To exclude the effect of telomere elongation, tail-tip fibroblasts (TTFs) from first generation TERT-KO mice were used. Although iPS cells were successfully generated from TERT-KO TTFs, the efficiency of reprogramming these cells was markedly lower than that of WT TTFs. The gene expression profiles of iPS cells induced from TERT-KO TTFs were similar to those of WT iPS cells and ES cells, and TERT-KO iPS cells formed teratomas that differentiated into all three germ layers. These data indicate that TERT plays an extratelomeric role in the reprogramming process, but its function is dispensable. However, TERT-KO iPS cells showed transient defects in growth and teratoma formation during continuous growth. In addition, TERT-KO iPS cells developed chromosome fusions that accumulated with increasing passage numbers, consistent with the fact that TERT is essential for the maintenance of genome structure and stability in iPS cells. In a rescue experiment, an enzymatically inactive mutant of TERT (D702A) had a positive effect on somatic cell reprogramming of TERT-KO TTFs, which confirmed the extratelomeric role of TERT in this process.
authors.affiliation: From the Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, 160-8582.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: From the Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, 160-8582, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, the Department of Stem Cell Biology and Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, gonag@hgs.med.kyushu-u.ac.jp.
authors.forename: Go
authors.initials: G
authors.lastname: Nagamatsu
authors.affiliation: Data Science Laboratory, OPT Inc., Tokyo, 102-0081, and.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.affiliation: From the Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, 160-8582.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: the Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Horimoto
authors.affiliation: From the Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, 160-8582.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D043171:Chromosomal Instability / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013623:Tail / Q000166:cytology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000502:physiology*; D013724:Teratoma / Q000201:enzymology* / Q000473:pathology
chemical_list: D019098:Telomerase; C509187:Tert protein, mouse
keywords: Bioinformatics; Induced Pluripotent Stem (iPS) Cell; Microarray; Reprogramming; Telomeres
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