Telomerase modulates Wnt signalling by association with target gene chromatin

• Published in: Nature (London) 2009-07, Vol.460 (7251), p.66-72
• Main Authors: Ji, Hong, Meng, Zhaojing, Venteicher, Andrew S, Hong, Ji Yeon, Park, Jae-Il, Choi, Jinkuk, Jun, Sohee, Veenstra, Timothy D, Chang, Woody, Cheung, Peggie, Artandi, Steven E, McCrea, Pierre D, Nusse, Roel, Shkreli, Marina, McLaughlin, Margaret
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; Binding sites; Biological and medical sciences; Cell division; Cell Line; Cell physiology; Cellular signal transduction; Choristoma - genetics; Choristoma - pathology; Chromatin; Chromatin - genetics; Chromatin. Chromosome; DNA Helicases - metabolism; Fundamental and applied biological sciences. Psychology; Gastrointestinal tract; Genes, Reporter - genetics; Glycoproteins; HeLa Cells; Humanities and Social Sciences; Humans; Intestine, Small - metabolism; Mice; Molecular and cellular biology; Molecular genetics; multidisciplinary; Nuclear Proteins - metabolism; Oocytes - cytology; Oocytes - growth & development; Physiological aspects; Plasmids - genetics; Promoter Regions, Genetic - genetics; Proteins; Science; Science (multidisciplinary); Signal Transduction; Small intestine; Somites - abnormalities; Somites - embryology; Stem cells; Telomerase; Telomerase - metabolism; Tissues; Transcription Factors - metabolism; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt3 Protein; Xenopus laevis; Xenopus laevis - embryology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08137

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. Telomerase link to Wnt signalling 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.