TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental Program

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 (TERTci) 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.

Actions of human telomerase beyond telomeres

“…More recent observations by Artandi and co-workers provides further support for a novel function of TERT in activating stem cells independent of telomerase activity [62]. They showed that TERT mutants lacking reverse transcriptase (RT) function retains the full activities in activating resting hair follicle stem cells and in enhancing keratinocyte proliferation in mouse skin, thereby inducing initiation of a new hair follicle growth phrase and promotes hair synthesis [62]. This study demonstrated that functions of TERT in the synthesis of telomere repeats and the novel function in stem cell behavior are genetically distinct.…”

“…Therefore these studies convincingly demonstrated that in addition to its established role in extending telomeres, TERT has its own activity in stem cell behavior independent of telomerase activity and telomere maintenance. More recent observations by Artandi and co-workers provides further support for a novel function of TERT in activating stem cells independent of telomerase activity [62]. They showed that TERT mutants lacking reverse transcriptase (RT) function retains the full activities in activating resting hair follicle stem cells and in enhancing keratinocyte proliferation in mouse skin, thereby inducing initiation of a new hair follicle growth phrase and promotes hair synthesis [62].…”

Epigenetic regulation of aging stem cells

“…Interestingly, distinct from its action in telomere maintenance, TERT regulates the mobilization and proliferation of epidermal stem cells in the hair follicle (Flores et al, 2005;Sarin et al, 2005). Consistent with its prominent role in stem cell proliferation independent of its reverse transcriptase activity, TERT is a pivotal component of the transcriptional complex downstream of WNT signaling (Choi et al, 2008;Park et al, 2009). In gastrointestinal tract stem cells, TERT interacts with the chromatin remodeling protein BRG1 and with b-catenin to activate essential WNT target genes (Park et al, 2009).…”

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

“…TERT expression in mouse skin caused a rapid transition of hair follicles from the telogen phase (quiescence) to the anagen phase (active growth), resulting in robust hair growth. This effect is associated with the growthpromoting gene expression programs related to the activation of c-myc and wnt transcriptional pathways (Choi et al, 2008;Park et al, 2009).…”