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Telomerase modulates Wnt signalling by association with target gene chromatin

Abstract

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/β-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/β-catenin signalling by serving as a cofactor in a β-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior–posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert-/- mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/β-catenin signalling pathway.

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Figure 1: TERT activates Wnt reporter plasmids in a BRG1-dependent manner.
Figure 2: TERT activates the Wnt pathway in vivo and is required for efficient target gene activation by WNT3A ligand in mouse ES cells.
Figure 3: TERT promotes anterior–posterior axis duplication and is required for efficient anterior–posterior axis in Xenopus.
Figure 4: Somite defects in Xenopus embryos treated with TERT morpholino and homeotic transformations in Tert -/- mice.
Figure 5: TERT occupies Wnt target gene promoters in HeLa cells and in mouse small intestine.

References

  1. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998)

    Article  CAS  PubMed  Google Scholar 

  3. Van Mater, D., Kolligs, F. T., Dlugosz, A. A. & Fearon, E. R. Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev. 17, 1219–1224 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lo Celso, C., Prowse, D. M. & Watt, F. M. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787–1799 (2004)

    Article  CAS  PubMed  Google Scholar 

  5. Sarin, K. Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flores, I., Cayuela, M. L. & Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253–1256 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45–51 (2007)

    Article  CAS  PubMed  Google Scholar 

  8. Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004)

    Article  CAS  PubMed  Google Scholar 

  10. Choi, J. et al. TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet. 4, e10 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  11. Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stewart, S. A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl Acad. Sci. USA 99, 12606–12611 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Smith, L. L., Coller, H. A. & Roberts, J. M. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nature Cell Biol. 5, 474–479 (2003)

    Article  CAS  PubMed  Google Scholar 

  15. Armstrong, L. et al. Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells 23, 516–529 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Imamura, S. et al. A non-canonical function of zebrafish telomerase reverse transcriptase is required for developmental hematopoiesis. PLoS ONE 3, e3364 (2008)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  17. Yang, C. et al. A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation, cell cycle dynamics, and in vitro differentiation. Stem Cells 26, 850–863 (2008)

    Article  CAS  PubMed  Google Scholar 

  18. Lee, J. et al. TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene 27, 3754–3760 (2008)

    Article  CAS  PubMed  Google Scholar 

  19. Masutomi, K. et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl Acad. Sci. USA 102, 8222–8227 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Venteicher, A. S., Meng, Z., Mason, P. J., Veenstra, T. D. & Artandi, S. E. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132, 945–957 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu, J. I., Lessard, J. & Crabtree, G. R. Understanding the words of chromatin regulation. Cell 136, 200–206 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu, Y. L. et al. Immunodetection of human telomerase reverse-transcriptase (hTERT) re-appraised: nucleolin and telomerase cross paths. J. Cell Sci. 119, 2797–2806 (2006)

    Article  CAS  PubMed  Google Scholar 

  23. Barker, N. et al. The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation. EMBO J. 20, 4935–4943 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Major, M. B. et al. New regulators of Wnt/β-catenin signaling revealed by integrative molecular screening. Sci Signal 1, ra12 (2008)

    PubMed  Google Scholar 

  25. Henriksson, M. & Luscher, B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res. 68, 109–182 (1996)

    Article  CAS  PubMed  Google Scholar 

  26. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998)

    Article  CAS  PubMed  Google Scholar 

  27. Lustig, B. et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol. Cell. Biol. 22, 1184–1193 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo . Nature 445, 661–665 (2007)

    CAS  PubMed  Google Scholar 

  29. McMahon, A. P. & Moon, R. T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell 58, 1075–1084 (1989)

    Article  CAS  PubMed  Google Scholar 

  30. Huelsken, J. et al. Requirement for β-catenin in anterior-posterior axis formation in mice. J. Cell Biol. 148, 567–578 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Heasman, J. et al. Overexpression of cadherins and underexpression of β-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell 79, 791–803 (1994)

    Article  CAS  PubMed  Google Scholar 

  32. Kao, K. R. & Elinson, R. P. The entire mesodermal mantle behaves as Spemann’ organizer in dorsoanterior enhanced Xenopus laevis embryos. Dev. Biol. 127, 64–77 (1988)

    Article  CAS  PubMed  Google Scholar 

  33. Yoshikawa, Y., Fujimori, T., McMahon, A. P. & Takada, S. Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev. Biol. 183, 234–242 (1997)

    Article  CAS  PubMed  Google Scholar 

  34. Dubrulle, J. & Pourquie, O. Coupling segmentation to axis formation. Development 131, 5783–5793 (2004)

    Article  CAS  PubMed  Google Scholar 

  35. Greco, T. L. et al. Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev. 10, 313–324 (1996)

    Article  CAS  PubMed  Google Scholar 

  36. Ikeya, M. & Takada, S. Wnt-3a is required for somite specification along the anteroposterior axis of the mouse embryo and for regulation of cdx-1 expression. Mech. Dev. 103, 27–33 (2001)

    Article  CAS  PubMed  Google Scholar 

  37. Pownall, M. E., Tucker, A. S., Slack, J. M. & Isaacs, H. V. eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus . Development 122, 3881–3892 (1996)

    CAS  PubMed  Google Scholar 

  38. Houle, M., Prinos, P., Iulianella, A., Bouchard, N. & Lohnes, D. Retinoic acid regulation of Cdx1: an indirect mechanism for retinoids and vertebral specification. Mol. Cell. Biol. 20, 6579–6586 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, H.-W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Erdmann, N., Liu, Y. & Harrington, L. Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice. Proc. Natl Acad. Sci. USA 101, 6080–6085 (2004)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lohnes, D. The Cdx1 homeodomain protein: an integrator of posterior signaling in the mouse. Bioessays 25, 971–980 (2003)

    Article  CAS  PubMed  Google Scholar 

  42. Farazi, P. A., Glickman, J., Horner, J. & Depinho, R. A. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 66, 4766–4773 (2006)

    Article  CAS  PubMed  Google Scholar 

  43. Rajaraman, S. et al. Telomere uncapping in progenitor cells with critical telomere shortening is coupled to S-phase progression in vivo . Proc. Natl Acad. Sci. USA 104, 17747–17752 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Willert, K. & Jones, K. A. Wnt signaling: is the party in the nucleus? Genes Dev. 20, 1394–1404 (2006)

    Article  CAS  PubMed  Google Scholar 

  45. Daniels, D. L. & Weis, W. I. β-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nature Struct. Mol. Biol. 12, 364–371 (2005)

    Article  CAS  Google Scholar 

  46. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547–551 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Carrera, I., Janody, F., Leeds, N., Duveau, F. & Treisman, J. E. Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13. Proc. Natl Acad. Sci. USA 105, 6644–6649 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, S., Xu, X., Hecht, A. & Boyer, T. G. Mediator is a transducer of Wnt/β-catenin signaling. J. Biol. Chem. 281, 14066–14075 (2006)

    Article  CAS  PubMed  Google Scholar 

  49. Wong, K.-K. et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nature Genet. 26, 85–88 (2000)

    Article  CAS  PubMed  Google Scholar 

  50. Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genomics Hum. Genet. 10.1146/annurev-genom-082908-150046 (2009)

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Acknowledgements

We thank P. Chu of the Stanford Comparative Medicine Histology Research Core Laboratory for technical assistance. We thank F. Ishikawa for Xenopus TERT plasmid, G. Crabtree for antibodies and plasmids, T. Jacks for ROSACreERT2 mice, and K. Park for constructive comments. J.-I.P. was supported by a Stanford Comprehensive Cancer Center Fellowship. This work was supported by NCI grants CA111691 and CA125453 and by a grant from the California Breast Cancer Research Program to S.E.A.

Author Contributions J.-I.P., A.S.V., J.Y.H., J.C., M.S., T.D.V., R.N., P.D.M. and S.E.A. designed the experiments and analysed data; J.-I.P., A.S.V., J.Y.H., J.C., S.J., M.S., W.C., Z.M., P.C., H.J. and M.M. performed the experiments; and J.-I.P. and S.E.A. wrote the manuscript.

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Correspondence to Steven E. Artandi.

Supplementary information

Supplementary information

This file contains Supplementary Methods, Supplementary Data, Supplementary Figures S1-S18 with Legends, Supplementary Tables 1-2 and Supplementary References. (PDF 3169 kb)

Supplementary Movie 1

This movie shows the skeletal system of TERT +/+ mouse. (MOV 2843 kb)

Supplementary Movie 2

This movie shows skeletal system of TERT-/- G1 mouse (unilateral T13 to L1 transformation). (MOV 2881 kb)

Supplementary Movie 3

This movie shows skeletal system of TERT-/- G1 mouse (complete T13 to L1 transformation). (MOV 2865 kb)

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Park, JI., Venteicher, A., Hong, J. et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66–72 (2009). https://doi.org/10.1038/nature08137

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