TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program

Jinkuk Choi, Lucinda K. Southworth, Kavita Y. Sarin, Andrew S. Venteicher, Wenxiu Ma, Woody Chang, Peggie Cheung, Sohee Jun, Maja K. Artandi, Naman Shah, Stuart K. Kim, Steven E. Artandi

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216 Scopus citations

Abstract

Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT ci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERTci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

Original languageEnglish (US)
Pages (from-to)124-138
Number of pages15
JournalPLoS genetics
Volume4
Issue number1
DOIs
StatePublished - Jan 2008

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    Choi, J., Southworth, L. K., Sarin, K. Y., Venteicher, A. S., Ma, W., Chang, W., Cheung, P., Jun, S., Artandi, M. K., Shah, N., Kim, S. K., & Artandi, S. E. (2008). TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS genetics, 4(1), 124-138. https://doi.org/10.1371/journal.pgen.0040010