Telomere Elongation in Induced Pluripotent Stem Cells from Dyskeratosis Congenita Patients

Overview

Journal Nature

Specialty Science

Date 2010 Feb 19

PMID 20164838

Citations 152

Authors

Suneet Agarwal

Yuin-Han Loh

Erin M McLoughlin

Junjiu Huang

In-Hyun Park

Justine D Miller

Hongguang Huo

Maja Okuka

Rosana Maria Dos Reis

Sabine Loewer

Huck-Hui Ng

David L Keefe

Frederick D Goldman

Aloysius J Klingelhutz

Lin Liu

George Q Daley

Affiliations

Soon will be listed here.

Abstract

Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells 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). 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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References

Atkinson S, Hoare S, Glasspool R, Keith W . Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res. 2005; 65(17):7585-90. DOI: 10.1158/0008-5472.CAN-05-1715. View

Calado R, Young N . Telomere maintenance and human bone marrow failure. Blood. 2008; 111(9):4446-55. PMC: 2343587. DOI: 10.1182/blood-2007-08-019729. View

Fu D, Collins K . Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol Cell. 2003; 11(5):1361-72. DOI: 10.1016/s1097-2765(03)00196-5. View

Yam P, Li S, Wu J, Hu J, Zaia J, Yee J . Design of HIV vectors for efficient gene delivery into human hematopoietic cells. Mol Ther. 2002; 5(4):479-84. DOI: 10.1006/mthe.2002.0558. View

Yi X, Tesmer V, Shay J, Wright W . Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Mol Cell Biol. 1999; 19(6):3989-97. PMC: 104358. DOI: 10.1128/MCB.19.6.3989. View

Kirwan M, Dokal I . Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet. 2007; 73(2):103-12. DOI: 10.1111/j.1399-0004.2007.00923.x. View

Li S, Rosenberg J, Donjacour A, Botchkina I, Hom Y, Cunha G . Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Cancer Res. 2004; 64(14):4833-40. DOI: 10.1158/0008-5472.CAN-04-0953. View

Greenberg M, Bender T . Identification of newly transcribed RNA. Curr Protoc Mol Biol. 2008; Chapter 4:Unit 4.10. DOI: 10.1002/0471142727.mb0410s78. View

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K . Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5):861-72. DOI: 10.1016/j.cell.2007.11.019. View

10.

Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T . A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol. 2007; 25(6):681-6. DOI: 10.1038/nbt1310. View

11.

Liu L, Bailey S, Okuka M, Munoz P, Li C, Zhou L . Telomere lengthening early in development. Nat Cell Biol. 2007; 9(12):1436-41. DOI: 10.1038/ncb1664. View

12.

Westin E, Chavez E, Lee K, Gourronc F, Riley S, Lansdorp P . Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts. Aging Cell. 2007; 6(3):383-94. PMC: 2225626. DOI: 10.1111/j.1474-9726.2007.00288.x. View

13.

Agarwal S, Rao A . Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1999; 9(6):765-75. DOI: 10.1016/s1074-7613(00)80642-1. View

14.

Montanaro L, Brigotti M, Clohessy J, Barbieri S, Ceccarelli C, Santini D . Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. J Pathol. 2006; 210(1):10-8. DOI: 10.1002/path.2023. View

15.

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

16.

Trahan C, Dragon F . Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP. RNA. 2008; 15(2):235-43. PMC: 2648702. DOI: 10.1261/rna.1354009. View

17.

Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek M . Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol. 1995; 155(8):3711-5. View

18.

Heiss N, Knight S, Vulliamy T, Klauck S, Wiemann S, Mason P . X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet. 1998; 19(1):32-8. DOI: 10.1038/ng0598-32. View

19.

Cawthon R . Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002; 30(10):e47. PMC: 115301. DOI: 10.1093/nar/30.10.e47. View

20.

Vaziri H, Benchimol S . Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol. 1998; 8(5):279-82. DOI: 10.1016/s0960-9822(98)70109-5. View