What question did this study set out to answer?

The study aims to investigate the non-telomeric roles of TRF2 in mouse neural stem cells and its impact on differentiation.

April 17, 2026

Non-telomeric TRF2 regulates differentiation-associated genes to maintain neural stem cell identity

Key Points

The study aims to investigate the non-telomeric roles of TRF2 in mouse neural stem cells and its impact on differentiation.
Used Trf2-deficient adult mNSCs to assess proliferation and differentiation.
Examined TRF2's binding to gene promoters and recruitment of the polycomb repressor complex.
Utilized G-quadruplex-binding ligands to evaluate the significance of G4 motifs in TRF2 function.
TRF2 depletion resulted in decreased proliferation and impaired neuronal differentiation in mNSCs.
No telomere dysfunction or DNA damage response was observed in Trf2-deficient mNSCs.
TRF2 was found to bind directly to differentiation-related gene promoters, facilitating repression through H3K27 trimethylation.

Abstract

Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere dysregulation or DNA damage response was observed. Similarly, TRF2 depletion in SH-SY5Y cells induced differentiation without telomere dysfunction. Mechanistically, non-telomeric TRF2 directly binds to the promoters of key genes that regulate differentiation, recruiting the polycomb repressor complex (PRC2) for H3K27 trimethylation, repressing differentiation genes to maintain NSC identity. G-quadruplex (G4) motifs are crucial for TRF2 binding; disrupting this interaction via G4-binding ligands or the G4-specific helicase DHX36 induces differentiation genes, promoting neurogenesis. These findings highlight TRF2's non-telomeric role in NSC survival, offering insights into neurogenesis and aging-related neurodegeneration.

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