Pharmaceutical Sciences Faculty Publications

Telomerase modulates Wnt signalling by association with target gene chromatin.

Document Type

Article

Publication Date

7-2-2009

Journal Title

Nature

ISSN

1476-4687

Volume

460

Issue

7251

First Page

66

Last Page

72

DOI

10.1038/nature08137

PubMed ID

19571879

PubMed Central® ID

PMC4349391

Abstract

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/beta-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/beta-catenin signalling by serving as a cofactor in a beta-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/beta-catenin signalling pathway.

Keywords

Cell line, choristoma, chromatin, DNA helicases, genes, intestine, nuclear proteins, oocytes, plasmids, promoter regions, genetic, signal transduction, somites, telomerase

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