Telomere regulation in pluripotent stem cells

Abstract

Pluripotent stem cells (PSCs) have the potential to produce any types of cells from all three basic germ layers and the capacity to self-renew and proliferate indefinitely in vitro. The two main types of PSCs, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), share common features such as colony morphology, high expression of Oct4 and Nanog, and strong alkaline phosphatase activity. In recent years, increasing evidences suggest that telomere length represents another important internal factor in maintaining stem cell pluripotency. Telomere length homeostasis and its structural integrity help to protect chromosome ends from recombination, end fusion, and DNA damage responses, ensuring the divisional ability of mammalian cells. PSCs generally exhibit high telomerase activity to maintain their extremely long and stable telomeres, and emerging data indicate the alternative lengthening of telomeres (ALT) pathway may play an important role in telomere functions too. Such characteristics are likely key to their abilities to differentiate into diverse cell types in vivo. In this review,we will focus on the function and regulation of telomeres in ESCs and iPSCs, thereby shedding light on the importance of telomere length to pluripotency and the mechanisms that regulate telomeres in PSCs.

Keywords

telomere / pluripotent stem cells / alternative lengthening of telomeres (ALT) / regulators

References

[1] Agarwal S, Loh YH, McLoughlin EM, Huang J, Park IH, Miller JD, Huo H, Okuka M, Dos Reis RM, Loewer S (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature464: 292-296

[2] Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Giri N, Lansdorp PM (2007) Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood110: 1439-1447

[3] Amano T, Hirata T, Falco G, Monti M, Sharova LV, Amano M, Sheer S, Hoang HG, Piao Y, Stagg CA (2013) Zscan4 restores the developmentalpotency ofembryonic stem cells. Nat Commun4: 1966

[4] Armstrong L, Saretzki G, Peters H, Wappler I, Evans J, Hole N, von Zglinicki T, Lako M (2005) Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells23: 516-529

[5] Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol8: 532-538

[6] Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L, Alter BP, Savage SA (2013) Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet132: 473-480

[7] Batista LF, Pech MF, Zhong FL, Nguyen HN, Xie KT, Zaug AJ, Crary SM, Choi J, Sebastiano V, Cherry A (2011) Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature474: 399-402

[8] Benetti R, Garcia-Cao M, Blasco MA (2007a) Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet39: 243-250

[9] Benetti R, Gonzalo S, Jaco I, Schotta G, Klatt P, Jenuwein T, Blasco MA (2007b) Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination. J Cell Biol178: 925-936

[10] Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol8: 1006-1016

[11] Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell125: 315-326

[12] Bessler M, Wilson DB, Mason PJ (2010) Dyskeratosis congenita. FEBS Lett584: 3831-3838

[13] Blasco MA (2007) Telomere length, stem cells and aging. Nat Chem Biol3: 640-649

[14] Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell91: 25-34

[15] Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR (1997) Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med3: 1271-1274

[16] Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S, Ganz K, Klemm SL, van Oudenaarden A, Jaenisch R (2012) Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell150: 1209-1222

[17] Cerone MA, Londono-Vallejo JA, Bacchetti S (2001) Telomere maintenance by telomerase and by recombination can coexist in human cells. Hum Mol Genet10: 1945-1952

[18] Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ (2002) Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci USA99: 3586-3590

[19] Cesare AJ, Reddel RR (2010) Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet11: 319-330

[20] Chang FT, McGhie JD, Chan FL, Tang MC, Anderson MA, Mann JR, Andy Choo KH, Wong LH (2013) PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells. Nucleic Acids Res41: 4447-4458

[21] Chen LY, Zhang Y, Zhang Q, Li H, Luo Z, Fang H, Kim SH, Qin L, Yotnda P, Xu J (2012) Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell47: 839-850

[22] Chung I, Osterwald S, Deeg KI, Rippe K (2012) PML body meets telomere: the beginning of an ALTernate ending? Nucleus3: 263-275

[23] Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR (2007) Protein composition of catalytically active human telomerase from immortal cells. Science315: 1850-1853

[24] Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev66: 407-425

[25] Coussens M, Davy P, Brown L, Foster C, Andrews WH, Nagata M, Allsopp R (2010) RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1alpha as critical for telomerase function in murine embryonic stem cells. Proc Natl Acad Sci USA107: 13842-13847

[26] Dang-Nguyen TQ, Haraguchi S, Furusawa T, Somfai T, Kaneda M, Watanabe S, Akagi S, Kikuchi K, Tajima A, Nagai T (2013) Downregulation of histone methyltransferase genes SUV39H1 and SUV39H2 increases telomere length in embryonic stem-like cells and embryonic fibroblasts in pigs. J Reprod Dev59: 27-32

[27] de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Gene Dev19: 2100-2110

[28] Drane P, Ouararhni K, Depaux A, Shuaib M, Hamiche A (2010) The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Gene Dev24: 1253-1265

[29] Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature292: 154-156

[30] Falco G, Lee SL, Stanghellini I, Bassey UC, Hamatani T, Ko MS (2007) Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol307: 539-550

[31] Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science309: 1253-1256

[32] Flores I, Canela A, Vera E, Tejera A, Cotsarelis G, Blasco MA (2008) The longest telomeres: a general signature of adult stem cell compartments. Genes Dev22: 654-667

[33] Garcia-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA (2004) Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet36: 94-99

[34] Giachino C, Orlando L, Turinetto V (2013) Maintenance of genomic stability in mouse embryonic stem cells: relevance in aging and disease. Int J Mol Sci14: 2617-2636

[35] Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo XY, Li X (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell140: 678-691

[36] Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AHFM, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol7: U420-U452

[37] Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol8: 416-424

[38] Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell43: 405-413

[39] Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature337: 331-337

[40] Hawkins RD, Hon GC, Lee LK, Ngo Q, Lister R, Pelizzola M, Edsall LE, Kuan S, Luu Y, Klugman S (2010) Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell6: 479-491

[41] Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science333: 425

[42] Henson JD, Hannay JA, McCarthy SW, Royds JA, Yeager TR, Robinson RA, Wharton SB, Jellinek DA, Arbuckle SM, Yoo JY (2005) A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res11: 217-225

[43] Herrera E, Samper E, Martin-Caballero J, Flores JM, Lee HW, Blasco MA (1999) Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J18: 2950-2960

[44] Hiyama E, Hiyama K (2007) Telomere and telomerase in stem cells. Br J Cancer96: 1020-1024

[45] Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R (2012) Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science336: 1549-1554

[46] Huang J, Wang F, Okuka M, Liu N, Ji G, Ye X, Zuo B, Li M, Liang P, Ge WW (2011) Association of telomere length with authentic pluripotency of ES/iPS cells. Cell Res21: 779-792

[47] Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature469: 102-106

[48] Ji G, Ruan W, Liu K, Wang F, Sakellariou D, Chen J, Yang Y, Okuka M, Han J, Liu Z (2013) Telomere reprogramming and maintenance in porcine iPS cells. PLoS One8: e74202

[49] Jiang L, Carter DB, Xu J, Yang X, Prather RS, Tian XC (2004) Telomere lengths in cloned transgenic pigs. Biol Reprod70: 1589-1593

[50] Jiang J, Lv W, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L (2013) Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res23: 92-106

[51] Kang L, Wang JL, Zhang Y, Kou ZH, Gao SR (2009) iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell5: 135-138

[52] Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature410: 116-120

[53] Lanza RP, Cibelli JB, Blackwell C, Cristofalo VJ, Francis MK, Baerlocher GM, Mak J, Schertzer M, Chavez EA, Sawyer N (2000) Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science288: 665-669

[54] Le R, Kou Z, Jiang Y, Li M, Huang B, Liu W, Li H, Kou X, He W, Rudolph KL, Ju Z, Gao S (2014) Enhanced telomere rejuvenation in pluripotent cells reprogrammed via nuclear transfer relative to induced pluripotent stem cells. Cell Stem Cell14: 27-39

[55] Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA107: 14075-14080

[56] Liu D, O’Connor MS, Qin J, Songyang Z (2004) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem279: 51338-51342

[57] Liu L, Bailey SM, Okuka M, Munoz P, Li C, Zhou L, Wu C, Czerwiec E, Sandler L, Seyfang A (2007) Telomere lengthening early in development. Nat Cell Biol9: 1436-1441

[58] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell153: 1194-1217

[59] Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JH, Sung PA, Jasin M (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet8: e1002772

[60] Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell1: 55-70

[61] Marion RM, Strati K, Li H, Tejera A, Schoeftner S, Ortega S, Serrano M, Blasco MA (2009) Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell4: 141-154

[62] Marion RM, Schotta G, Ortega S, Blasco MA (2011) Suv4-20h abrogation enhances telomere elongation during reprogramming and confers a higher tumorigenic potential to iPS cells. PLoS One6: e25680

[63] Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA78: 7634-7638

[64] Mason PJ, Wilson DB, Bessler M (2005) Dyskeratosis congenita—a disease of dysfunctional telomere maintenance. Curr Mol Med5:159-170

[65] Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T (2006) Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell10: 105-116

[66] Mikkelsen TS, Hanna J, Zhang XL, Ku MC, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature454: U41-U49

[67] Neuman(n AA, Watson CM, Noble JR, Pickett HA, Tam PP, Reddel RR (2013) Alternative lengthening of telomeres in normal mammalian somatic cells. Genes Dev27: 18-23

[68] Niida H, Shinkai Y, Hande MP, Matsumoto T, Takehara S, Tachibana M, Oshimura M, Lansdorp PM, Furuichi Y (2000) Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA. Mol Cell Biol20: 4115-4127

[69] Papp B, Plath K (2013) Epigenetics of reprogramming to induced pluripotency. Cell152: 1324-1343

[70] Pucci F, Gardano L, Harrington L (2013) Short telomeres in ESCs lead to unstable differentiation. Cell Stem Cell12: 479-486

[71] Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature470: 359-365

[72] Scheel C, Schaefer KL, Jauch A, Keller M, Wai D, Brinkschmidt C, van Valen F, Boecker W, Dockhorn-Dworniczak B, Poremba C (2001) Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene20: 3835-3844

[73] Schneider RP, Garrobo I, Foronda M, Palacios JA, Marion RM, Flores I, Ortega S, Blasco MA (2013) TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells. Nat Commun4: 1946

[74] Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature482: 226-231

[75] Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer33: 787-791

[76] Shiels PG, Kind AJ, Campbell KH, Waddington D, Wilmut I, Colman A, Schnieke AE (1999) Analysis of telomere lengths in cloned sheep. Nature399: 316-317

[77] Sparman M, Dighe V, Sritanaudomchai H, Ma H, Ramsey C, Pedersen D, Clepper L, Nighot P, Wolf D, Hennebold J (2009) Epigenetic reprogramming by somatic cell nuclear transfer in primates. Stem Cells27: 1255-1264

[78] Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126: 663-676

[79] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131: 861-872

[80] Tejera AM, Stagno d'Alcontres M, Thanasoula M, Marion RM, Martinez P, Liao C, Flores JM, Tarsounas M, Blasco MA (2010) TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice. Dev Cell18: 775-789

[81] Varela E, Schneider RP, Ortega S, Blasco MA (2011) Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells. Proc Natl Acad Sci USA108: 15207-15212

[82] Walne AJ, Dokal I (2009) Advances in the understanding of dyskeratosis congenita. Br J Haematol145: 164-172

[83] Wang F, Yin Y, Ye X, Liu K, Zhu H, Wang L, Chiourea M, Okuka M, Ji G, Dan J (2012) Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells. Cell Res22: 757-768

[84] Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP (2009) Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet41: 246-250

[85] Winkler T, Hong SG, Decker JE, Morgan MJ, Wu C, Hughes WMt, Yang Y, Wangsa D, Padilla-Nash HM, Ried T (2013) Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs. J Clin Invest123: 1952-1963

[86] Wong LH, Ren H, Williams E, McGhie J, Ahn S, Sim M, Tam A, Earle E, Anderson MA, Mann J (2009) Histone H3.3 incorporation provides a unique and functionally essential telomeric chromatin in embryonic stem cells. Genome Res19: 404-414

[87] Wong CW, Hou PS, Tseng SF, Chien CL, Wu KJ, Chen HF, Ho HN, Kyo S, Teng SC (2010a) Kruppel-like transcription factor 4 contributes to maintenance of telomerase activity in stem cells. Stem Cells28: 1510-1517

[88] Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, George AJ, Morgan KA, Mann JR, Choo KH (2010b) ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells. Genome Res20: 351-360

[89] Xin HW, Liu D, Wan M, Safari A, Kim H, Sun W, O’Connor MS, Zhou SY (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature445: 559-562

[90] Xin H, Liu D, Songyang Z (2008) The telosome/shelterin complex and its functions. Genome Biol9: 232

[91] Yang CB, Przyborski S, Cooke MJ, Zhang X, Stewart R, Anyfantis G, Atkinson SP, Saretzki G, Armstrong L, Lako M (2008) A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation, cell cycle dynamics, and in vitro differentiation. Stem Cells26: 850-863

[92] Yehezkel S, Rebibo-Sabbah A, Segev Y, Tzukerman M, Shaked R, Huber I, Gepstein L, Skorecki K, Selig S (2011) Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives. Epigenetics6: 63-75

[93] Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE (2010) Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature464: 858-863

[94] Zeng S, Liu L, Sun Y, Xie P, Hu L, Yuan D, Chen D, Ouyang Q, Lin G, Lu G (2013) Telomerase-mediated telomere elongation from human blastocysts to embryonic stem cells. J Cell Sci. doi:10. 1242/jcs.131433

[95] Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L (2009) iPS cells produce viable mice through tetraploid complementation. Nature461: U86-U88

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