Clonal inactivation of TERT impairs stem cell competition

Kazuteru Hasegawa, Yang Zhao, Alina Garbuzov, M. Ryan Corces, Patrick Neuhöfer, Victoria M. Gillespie, Peggie Cheung, Julia A. Belk, Yung-Hsin Huang, Yuning Wei, Lu Chen, Howard Y. Chang and Steven E. Artandi ()
Additional contact information
Kazuteru Hasegawa: Stanford University School of Medicine
Yang Zhao: Center for Personal Dynamic Regulomes
Alina Garbuzov: Stanford University School of Medicine
M. Ryan Corces: Center for Personal Dynamic Regulomes
Patrick Neuhöfer: Stanford University School of Medicine
Victoria M. Gillespie: Fox Chase Cancer Center
Peggie Cheung: Stanford University School of Medicine
Julia A. Belk: Stanford University
Yung-Hsin Huang: Center for Personal Dynamic Regulomes
Yuning Wei: Center for Personal Dynamic Regulomes
Lu Chen: Stanford University School of Medicine
Howard Y. Chang: Center for Personal Dynamic Regulomes
Steven E. Artandi: Stanford University School of Medicine

Nature, 2024, vol. 632, issue 8023, 201-208

Abstract: Abstract Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres—nucleoprotein caps that protect chromosome ends1. Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner2–8, but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function. In many tissues, homeostasis is shaped by stem cell competition, a process in which stem cells compete on the basis of inherent fitness. Here we show that conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation. Using lineage tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin. This role for TERT in competitive clone formation occurs independently of both its reverse transcriptase activity and the canonical telomerase complex. Inactivation of TERT causes reduced activity of the MYC oncogene, and transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation. Together, these data reveal a catalytic-activity-independent requirement for TERT in enhancing stem cell competition, uncover a genetic connection between TERT and MYC and suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and ageing.

Date: 2024
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DOI: 10.1038/s41586-024-07700-w

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