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Clonal inactivation of TERT impairs stem cell competition
Kazuteru Hasegawa1,2,3, Yang Zhao4, Alina Garbuzov1,2,3
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|July 17, 2024
Summary
Telomerase reverse transcriptase (TERT) enhances stem cell competition independently of its catalytic function. TERT influences stem cell fate and MYC oncogene activity, impacting clone formation and genome regulation.
Area of Science:
- Stem cell biology
- Cancer research
- Epigenetics
Background:
- Telomerase, including telomerase reverse transcriptase (TERT), is linked to stem cells and cancer due to its role in telomere elongation.
- While TERT overexpression affects cell proliferation, its direct role in stem cell function has been unclear.
- Stem cell competition is a key factor in tissue homeostasis.
Purpose of the Study:
- To investigate the role of TERT in stem cell competition, independent of its catalytic activity.
- To explore the mechanisms by which TERT influences stem cell fitness and differentiation.
- To uncover potential genetic links between TERT and other key regulatory genes.
Main Methods:
- Conditional deletion of Tert in mouse spermatogonial stem cells (SSCs).
- Lineage tracing to track TERT-expressing and TERT-inactivated SSCs.
- Analysis of clone formation, stem cell differentiation, and chromatin accessibility.
- Investigation of MYC oncogene activity in TERT-manipulated SSCs.
Main Results:
- Conditional Tert deletion in SSCs significantly impaired competitive clone formation.
- TERT-expressing SSCs formed long-lived clones, while TERT inactivation promoted differentiation and reduced open chromatin.
- TERT's role in stem cell competition was independent of its reverse transcriptase activity and the telomerase complex.
- TERT inactivation reduced MYC oncogene activity, which could be rescued by MYC overexpression.
Conclusions:
- TERT is required for enhancing stem cell competition through a mechanism independent of its catalytic activity.
- A genetic link between TERT and the MYC oncogene was identified, influencing stem cell fate.
- High TERT levels confer a selective advantage to stem cells, contributing to telomere maintenance in the male germline.
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