Telomeres control human telomerase (TERT) expression through non-telomeric TRF2.

🥈 Top 2% JournalSep 30, 2025eLife

Telomeres regulate human telomerase levels through TRF2 acting outside telomeres

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Abstract

Telomere length (TL) influences transcriptional regulation, with significant changes observed across various cell lines.

Transcriptional activity was altered based on telomere length, with specific binding of TRF2 to promoters observed.
Cell lines engineered for telomere elongation showed increased transcription, while those with shortened telomeres exhibited decreased transcription.
Promoter-bound TRF2 recruits a repressor complex that modifies histones in a manner dependent on telomere length.
During reprogramming of fibroblasts to induced pluripotent stem cells, telomere elongation caused loss of TRF2 from the promoter and increased transcription.
Conversely, telomere shortening in induced pluripotent stem cells led to restoration of TRF2 at the promoter, correlating with reduced transcription.

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The function of the human telomerase reverse transcriptase (referred hereafter as) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influenceregulation is relatively less studied. We foundwas transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and thepromoter.promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to thepromoter. Cell lines from different tissue types fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening, gave an increase/decrease in, respectively. Mechanistically, we showpromoter-bound non-telomeric TRF2 recruits the canonical PRC2-complex, inducing repressor histone H3K27-trimethylation in a TL-dependent fashion. This was further supported by TL-dependent promoter activity from an exogenously insertedreporter. Increase in TL over days followed by a gradual decline, resulted in activation followed by repression ofin a concerted manner, further implicating TL as a key factor forregulation. Notably, on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from thepromoter was evident along with telomere elongation andupregulation. Conversely, on telomere shortening in iPSCs,promoter-bound TRF2 was restored with a marked reduction infurther supporting the causal role of TL intranscription. Mechanisms of tight control ofby TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency. TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT TERT, TERT TERT

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