Abstract

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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Acknowledgements

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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Affiliations

  1. Division of Hematology/Oncology, Children’s Hospital Boston; Pediatric Oncology, Dana Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Division of Hematology, Brigham and Women’s Hospital; Harvard Stem Cell Institute; Manton Center for Orphan Disease Research; Boston, Massachusetts 02115, USA

    • Suneet Agarwal
    • , Yuin-Han Loh
    • , Erin M. McLoughlin
    • , In-Hyun Park
    • , Justine D. Miller
    • , Hongguang Huo
    • , Sabine Loewer
    •  & George Q. Daley
  2. Department of Obstetrics and Gynecology, MDC 3125, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, USA

    • Junjiu Huang
    • , Maja Okuka
    • , Rosana Maria dos Reis
    • , David L. Keefe
    •  & Lin Liu
  3. State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China

    • Junjiu Huang
  4. Gene Regulatory Laboratory, Genome Institute of Singapore; Department of Biological Sciences, National University of Singapore; 60 Biopolis Street, #02-01, Genome, Singapore 138672

    • Huck-Hui Ng
  5. Department of Pediatrics, The Children’s Hospital of Alabama, 1600 7th Avenue South, ACC 512, Birmingham, Alabama 35233, USA

    • Frederick D. Goldman
  6. Department of Microbiology, University of Iowa, 2202 MERF, 375 Newton Road, Iowa City, Iowa 52242, USA

    • Aloysius J. Klingelhutz
  7. College of Life Sciences, Nankai University, Tianjin 300071, China

    • Lin Liu
  8. Howard Hughes Medical Institute, Children’s Hospital Boston, Karp Family Research Building 07214, 1 Blackfan Circle, Boston, Massachusetts 02115, USA

    • George Q. Daley

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Competing interests

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

Corresponding author

Correspondence to George Q. Daley.

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https://doi.org/10.1038/nature08792

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