Clonal Inactivation of Telomerase Reverse Transcriptase (TERT) Impairs Stem Cell Competition in Mice

Core Concepts

Conditional deletion of the Tert gene in the spermatogonial stem cell (SSC) population of mice impairs competitive clone formation, promotes stem cell differentiation, and reduces genome-wide open chromatin, independent of TERT's reverse transcriptase activity and the canonical telomerase complex.

Abstract

The article investigates the role of telomerase reverse transcriptase (TERT) in stem cell competition and function. Telomerase is closely associated with stem cells and cancer, as it catalytically elongates telomeres, which protect chromosome ends.

The key findings are:

1. Conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation.
2. Lineage tracing from the Tert locus shows that TERT-expressing SSCs yield long-lived clones, but clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin.
3. This role of TERT in competitive clone formation occurs independently of its reverse transcriptase activity and the canonical telomerase complex.
4. 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.
5. The findings suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and aging.

Stats

Conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation.
Clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin.
Inactivation of TERT causes reduced activity of the MYC oncogene.
Transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation.

Quotes

"Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres—nucleoprotein caps that protect chromosome ends."
"Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner, but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function."
"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."

Key Insights Distilled From

Clonal inactivation of TERT impairs stem cell competition - Nature

by Kazuteru Has... at www.nature.com 07-17-2024

https://www.nature.com/articles/s41586-024-07700-w

Deeper Inquiries

How might the insights from this study on the role of TERT in stem cell competition be applied to develop new therapeutic strategies for cancer or other stem cell-related diseases?

The findings from this study suggest that TERT plays a crucial role in enhancing stem cell competition independent of its catalytic activity. This opens up new possibilities for targeting TERT in stem cell populations to modulate their behavior. One potential therapeutic strategy could involve developing small molecules or inhibitors that specifically target the non-canonical functions of TERT in stem cells. By disrupting the interaction between TERT and other key regulators like MYC, it may be possible to alter the competitive dynamics of stem cell populations, potentially inhibiting the growth of cancer stem cells or promoting the regeneration of healthy tissues. Additionally, understanding the genetic connections between TERT and MYC could lead to the development of combination therapies that target both pathways simultaneously, offering a more effective treatment approach for diseases involving dysregulated stem cell populations.

What other cellular pathways or mechanisms might be involved in the catalytic-activity-independent function of TERT in enhancing stem cell competition?

The study highlights a novel role for TERT in promoting stem cell competition that is independent of its canonical telomerase activity. Several cellular pathways and mechanisms may be involved in mediating this function of TERT. One potential pathway could be the regulation of gene expression through interactions with transcription factors or chromatin modifiers. TERT may influence the epigenetic landscape of stem cells, leading to changes in gene expression patterns that affect their competitive fitness. Additionally, TERT could be involved in signaling pathways that control stem cell behavior, such as the Wnt or Notch pathways, which are known to regulate stem cell self-renewal and differentiation. Understanding the crosstalk between TERT and these pathways could provide further insights into the mechanisms underlying its role in enhancing stem cell competition.

Given the connection between TERT and MYC uncovered in this study, how might the interplay between these two factors influence broader aspects of stem cell biology and tissue homeostasis?

The discovery of a genetic connection between TERT and MYC in regulating stem cell competition has significant implications for broader aspects of stem cell biology and tissue homeostasis. MYC is a well-known oncogene that plays a critical role in cell proliferation and survival, and its dysregulation is associated with various cancers. The interplay between TERT and MYC could influence the balance between stem cell self-renewal and differentiation, impacting tissue regeneration and maintenance. By modulating the activity of MYC in TERT-deleted stem cells, it may be possible to restore their competitive advantage and promote tissue homeostasis. Furthermore, the TERT-MYC axis may serve as a potential therapeutic target for manipulating stem cell behavior in regenerative medicine or cancer therapy, offering new avenues for intervention in diseases characterized by aberrant stem cell function.