Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients

Agarwal, Suneet; Loh, Yuin-Han; McLoughlin, Erin M.; Huang, Junjiu; Park, In‐Hyun; Miller, Joseph S.; Huo, Hongguang; Okuka, Maja; Reis, Rosana Maria dos; Loewer, Sabine; Ng, Huck‐Hui; Keefe, David L.; Goldman, Frederick D.; Klingelhutz, Aloysius J.; Liu, Lin; Daley, George Q.

doi:10.1038/nature08792

Cited by 293 publications

(237 citation statements)

References 38 publications

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“…iPS-5 P8-14 with elongated telomeres generated chimeras at rates lower than iPS-6 P36-45, and higher than iPS P8-16. These data show that some iPSC lines undergo telomere lengthening during iPS induction and culture following passaging, consistent with previous reports in humans and mice [21,22]. However, a few iPSCs failed to elongate telomeres, particularly at early passages, despite their expression of Oct4 and Nanog, and the ability to form teratomas.…”

Section: Association Of Telomere Length With Pluripotency Of Ipscssupporting

confidence: 92%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells (iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells (ESCs) or iPSCs, however, has not been directly addressed. We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated (r > 0.8) with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics, down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible.

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Section: Association Of Telomere Length With Pluripotency Of Ipscssupporting

confidence: 92%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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“…In the past 12 years, elegant studies have revealed mutations in seven genes as a cause of DC, all of which encode telomerase (DKC1, TERT, TERC, NOP10, NHP2, TCAB1) or telomere structural (TINF2) components. Moreover, mutations in some of these genes have been found in familial degenerative disorders without classical DC, including aplastic anemia, myelodysplastic syndrome, and idiopathic pulmonary fibrosis [5] [6,7]. A comparison of the data in these two reports illustrates the advantages and limitations of the iPS approach for modeling human diseases.…”

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confidence: 96%

Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

Agarwal

Daley²

2011

Cell Res

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“…During reprogramming, TERT is activated and telomerase activity is reconstituted. 59,60 However, this may not be sufficient to rescue all classes of DC patient cells. For example, iPS cell reprogramming of DC patient cells harboring a mutation in TCAB1, a telomerase-associated protein that facilitates trafficking of telomerase to Cajal bodies, [61][62][63] showed that despite wild-type telomerase activity, the ability of telomerase to elongate telomeres was abrogated, because telomerase was mislocalized.…”

Section: Tin2 Hp1 and Telomere Elongation By Telomerasementioning

confidence: 99%

A role for sister telomere cohesion in telomere elongation by telomerase

Houghtaling

Canudas²,

Smith

2012

Cell Cycle

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T elomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC), a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and, further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.

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Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients

Cited by 293 publications

References 38 publications

Association of telomere length with authentic pluripotency of ES/iPS cells

Association of telomere length with authentic pluripotency of ES/iPS cells

Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

A role for sister telomere cohesion in telomere elongation by telomerase

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