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. The Wnt/β-catenin signalling pathway plays a central role in stem cell biology and has been implicated in tumorigenesis. Telomerase-catalysed addition of DNA repeats to chromosome ends is crucial for stem cell self-renewal and for progenitor cell survival and has also been implicated in tumorigenesis. Park et al. report an unanticipated link between these two pathways with prominent roles in tissue stem cells and cancer. The telomerase component TERT (telomerase reverse transcriptase) is shown act as a transcriptional modulator of the Wnt/β-catenin signalling pathway. The chromatin remodelling protein BRG1, a modulator of Wnt signalling, is identified as a TERT-interacting protein. The genetic pathways controlling stem cells are frequently dysregulated during tumorigenesis, with either stimulation of Wnt/β-catenin signalling or overexpression of telomerase sufficient to activate epidermal stem cells in vivo. Here, the telomerase protein component TERT (telomerase reverse transcriptase) is shown to have a role as a transcriptional modulator of the Wnt/β-catenin pathway, revealing a significant level of integration between the two pathways.