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Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients


Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues1,2,3. Patient-specific induced pluripotent stem (iPS) cells4 represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)5,6,7. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.

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Figure 1: Derivation and characterization of DKC1 mutant iPS cells.
Figure 2: Telomere elongation in DKC1 mutant iPS cells.
Figure 3: Upregulation of TERC and DKC1 in iPS cells.
Figure 4: Transcriptional silencing is associated with a 3′ deletion in the TERC locus.

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This work was funded by grants from the National Institutes of Health (NIH) and the Manton Center for Orphan Disease Research (G.Q.D.); NIH K08HL089150, Amy Clare Potter Fellowship and Manton Center for Orphan Disease Research (S.A.); the Agency of Science, Technology and Research and the Institute of Medical Biology, Singapore (Y.-H.L.); NIH R01AG0227388 (F.D.G. and A.J.K.); and the James and Esther King Biomedical Research Program and MOST 973 project (2009CB941000) (D.L.K and L.L).

Author Contributions S.A. performed project planning, experimental work, data interpretation and preparation of the manuscript. Y.-H.L., I.-H.P., J.H., E.M.M., J.D.M., R.M.R., M.O., H.H. and S.L. performed experimental work. H.-H.N., F.D.G., D.L.K., A.J.K., L.L. and G.Q.D. participated in project planning, data interpretation and preparation of the manuscript.

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Correspondence to George Q. Daley.

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George Q. Daley is a member of the scientific advisory boards of MPM Capital, Epizyme, Inc., and iPierian, Inc.

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Agarwal, S., Loh, YH., McLoughlin, E. et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).

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