Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives

Yehezkel, Shiran; Rebibo-Sabbah, Annie; Segev, Yardena; Tzukerman, Maty; Shaked, Rony; Huber, Irit; Gepstein, Lior; Skorecki, Karl; Selig, Sara

doi:10.4161/epi.6.1.13390

Cited by 73 publications

(79 citation statements)

References 65 publications

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“…MYC and KLF-4, 2 of the transcription factors commonly used to derive iPSCs and endogenously upregulated following reprogramming, directly or indirectly induce TERT expression (30,34). Reprogramming is associated with de novo changes in methylation of subtelomeric chromosomal regions and elevation of telomeric-repeat-containing RNA (TERRA) expression, indicating that significant changes in the architecture and function of telomeric and subtelomeric structures take place during this process (19).…”

Section: Figurementioning

confidence: 99%

“…The induction of telomerase expression and resultant telomere elongation occur following reprogramming of somatic cells to pluripotency in both murine (18) and human (19) iPSCs. MYC and KLF-4, 2 of the transcription factors commonly used to derive iPSCs and endogenously upregulated following reprogramming, directly or indirectly induce TERT expression (30,34).…”

Section: Figurementioning

confidence: 99%

“…High expression of telomerase in human ES cells ensures maintenance of telomere length and helps define their pluripotent phenotype (15). Telomerase is also upregulated during iPSC generation (16,17) and is likely responsible for telomere elongation and maintenance in these cells (18,19). Therefore, reprogramming technology followed by differentiation could be a valuable tool for studying telomere dynamics in a mutation-and patient-specific manner.…”

Section: Introductionmentioning

confidence: 99%

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Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Winkler

Hong²,

Decker³

et al. 2013

J. Clin. Invest.

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Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and leading to malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of human diseases. We derived induced pluripotent stem cells (iPSCs) from 4 patients with aplastic anemia or hypocellular bone marrow carrying heterozygous mutations in the telomerase reverse transcriptase (TERT) or the telomerase RNA component (TERC) telomerase genes. Both mutant and control iPSCs upregulated TERT and TERC expression compared with parental fibroblasts, but mutant iPSCs elongated telomeres at a lower rate compared with healthy iPSCs, and the deficit correlated with the mutations' impact on telomerase activity. There was no evidence for alternative lengthening of telomere (ALT) pathway activation. Elongation varied among iPSC clones derived from the same patient and among clones from siblings harboring identical mutations. Clonal heterogeneity was linked to genetic and environmental factors, but was not influenced by residual expression of reprogramming transgenes. Hypoxia increased telomere extension in both mutant and normal iPSCs. Additionally, telomerase-mutant iPSCs showed defective hematopoietic differentiation in vitro, mirroring the clinical phenotype observed in patients and demonstrating that human telomere diseases can be modeled utilizing iPSCs. Our data support the necessity of studying multiple clones when using iPSCs to model disease.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Winkler

Hong²,

Decker³

et al. 2013

J. Clin. Invest.

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show abstract

“…It was demonstrated that iPSCs could not be generated from somatic cells from late generations (G3) of telomerase-null mice, possibly due to the high degrees of genomic instability as a result of telomere fusions, and that reintroduction of telomerase could restore the efficiency of generating iPSCs [50] . Interestingly, iPSCs derived from normal human and mouse cells show progressive telomere elongation with passaging in cultures, indicating that telomere elongation can occur postprogramming [50][51][52][53] . Studies have also shown that telomerase enzymatic activity is significantly activated upon iPS manipulation [38][39][40]50,52,54] as a result of upregulated expression of the TERT protein and TERC RNA, as well as of the associated protein dyskerin [52,54] .…”

Section: Effects Of Cloning On Telomeres and Telomerase Of Normal Cellsmentioning

confidence: 99%

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

Ly¹

2011

WJG

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Recent advances in reprograming somatic cells from normal and diseased tissues into induced pluripotent stem cells (iPSCs) provide exciting possibilities for generating renewed tissues for disease modeling and therapy. However, questions remain on whether iPSCs still retain certain markers (e.g. aging) of the original somatic cells that could limit their replicative potential and utility. A reliable biological marker for measuring cellular aging is telomere length, which is maintained by a specialized form of cellular polymerase known as telomerase. Telomerase is composed of the cellular reverse transcriptase protein, its integral RNA component, and other cellular proteins (e.g. dyskerin). Mutations in any of these components of telomerase can lead to a severe form of marrow deficiency known as dyskeratosis congenita (DC). This review summarizes recent findings on the effect of cellular reprograming via iPS of normal or DC patient-derived tissues on telomerase function and consequently on telomere length maintenance and cellular aging. The potentials and challenges of using iPSCs in a clinical setting will also be discussed.

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“…During the telomeric crisis towards immortalization a series of marked changes should occur accompanied by the reorganization of chromosomes. These changes may include epigenetic ones around telomeric regions as observed during the generation of human pluripotent stem cells (17).…”

Section: Role Of Wrn Gene In Breakage-fusion-bridge Cycle At Telomerimentioning

confidence: 99%

Involvement of WRN helicase in immortalization and tumorigenesis by the telomeric crisis pathway (Review)

et al. 2011

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Abstract. The repeated replication of cells shortens telomeres, culminating in their instability, after which most cells cease to replicate and die. However, a small fraction of the cells become immortalized by maintaining telomeres with activated telomerase activity. It has been proposed that WRN helicase encoded by the WRN gene, the causative gene of Werner syndrome (WS), is required for immortalization by the telomeric crisis pathway (TCP) in a system that uses lymphoblastoid cell lines transformed by the Epstein-Barr virus. Taken together, these characteristics indicate that WRN helicase is also required for the immortalization of epithelial cells by TCP and consequent carcinogenesis, suggesting that the tumorigenesis of epithelial cells by TCP is suppressed in WS lacking the WRN helicase function. Notably, in WS the pathway of alternative lengthening of telomeres without activation of telomerase activity has been suggested to be involved in immortalization and tumorigenesis. This factor is consistent with the abundance of non-epithelial cancers in WS in that the ratio of epithelial to non-epithelial cancers is approximately 1:1 in WS patients compared to 10:1 in the general population. A hypothetical scheme showing the role of WRN helicase in immortalization by means of the supposed 'breakage-fusionbridge cycle' of chromosomes at telomeric crisis is described. IntroductionThe Werner syndrome (WS) is an autosomal recessive disorder causing symptoms of premature aging (1). The causative gene of WS is the WRN gene encoding for WRN protein, a DNA helicase (2). Another characteristic feature of this disorder is a much higher incidence of rare cancers (3). Non-epithelial tumors, including soft-tissue sarcoma and benign meningioma, are associated with WS, as shown by 124 case reports of neoplasia of WS patients from Japan, and 34 case reports from outside Japan between 1939 and August 1995. Notably, the ratio of epithelial to non-epithelial cancers was approximately 1:1 in WS patients compared to 10:1 in the general population. Two telomere maintenance mechanisms, telomerase activation (4) and alternative lengthening of telomeres (ALT) (5,6) exist. In human tumors of the general population over 80% of carcinomas maintain telomeres by telomerase activation, whereas various types of sarcomas elongate telomeres by means of ALT in the absence of telomerase activity (7). In tumors in WS patients, however, evidence has shown that the telomerase activation pathway by telomeric crisis is blocked, while the ALT pathway is enhanced (8-10), supporting the high incidence of rare cancers in WS. Role of WRN gene in immortalization by means of telomeric crisis pathwayThe repeated replication of cells shortens telomeres, culminating in their instability, after which most cells cease to replicate and die. However, a small fraction of the cells become immortalized by maintaining telomeres with activated telomerase activity, known as the telomeric crisis pathway (TCP) (11)(12)(13)

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Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives

Cited by 73 publications

References 65 publications

Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

Involvement of WRN helicase in immortalization and tumorigenesis by the telomeric crisis pathway (Review)

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