Telomerase modulates Wnt signalling by association with target gene chromatin

Jae-Il Park, Andrew S. Venteicher, Ji Yeon Hong, Jinkuk Choi, Sohee Jun, Marina Shkreli, Woody Chang, Zhaojing Meng, Peggie Cheung, Hong Ji, Margaret McLaughlin, Timothy D. Veenstra, Roel Nusse, Pierre D. McCrea and Steven E. Artandi ()
Additional contact information
Jae-Il Park: Department of Medicine,
Andrew S. Venteicher: Department of Medicine,
Ji Yeon Hong: University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Jinkuk Choi: Department of Medicine,
Sohee Jun: Department of Medicine,
Marina Shkreli: Department of Medicine,
Woody Chang: Department of Medicine,
Zhaojing Meng: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland 21702, USA
Peggie Cheung: Department of Medicine,
Hong Ji: University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Margaret McLaughlin: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Timothy D. Veenstra: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland 21702, USA
Roel Nusse: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
Pierre D. McCrea: University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
Steven E. Artandi: Department of Medicine,

Nature, 2009, vol. 460, issue 7251, 66-72

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08137

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