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.

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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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