The function of the human telomerase reverse transcriptase (referred hereafter as TERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influence TERT regulation is relatively less studied. We found TERT was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the TERT promoter. TERT promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to the TERT promoter. 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 TERT, respectively. Mechanistically, we show TERT promoter-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 inserted TERT reporter. Increase in TL over days followed by a gradual decline, resulted in activation followed by repression of TERT in a concerted manner, further implicating TL as a key factor for TERT regulation. Notably, on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from the TERT promoter was evident along with telomere elongation and TERT upregulation. Conversely, on telomere shortening in iPSCs, TERT promoter-bound TRF2 was restored with a marked reduction in TERT, further supporting the causal role of TL in TERT transcription. Mechanisms of tight control of TERT by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency.
Keywords: TRF2; cancer; cancer biology; chromosomes; epigenetics; gene expression; human; telomerase; telomere.
Human cells typically have 23 pairs of structures known as chromosomes, each containing a unique set of genes that provides the instructions needed to make proteins and other essential molecules found in the body. At the end of each chromosome lies a region of repetitive DNA sequences, known as the telomere, which protects the chromosome strands from damage or tangling. Every time a cell divides, some of the telomere repeats are cut off, causing the telomeres to shorten. Specific enzymes known as telomerases can add these repeats back on so that the telomeres do not become too short. As we age, telomeres naturally shorten in length, but certain lifestyle factors can accelerate this process, leading to programmed cell death and contributing to various diseases, including cancers. In 2018, researchers showed that TRF2, a key telomere protein, helps relay information about telomere length to various regulatory genes. However, it remained unclear whether TRF2 could directly communicate this information to the telomerase itself. Sengupta et al. – including several of the researchers from the 2018 study – set out to answer this question by studying multiple human cancer cell lines with different telomere lengths. They discovered that TRF2 acts like a messenger that interacts with the telomerase gene TERT, in a length-dependent manner. When telomeres were long, most TRF2 remained bound at the telomeres and did not interact with TERT, allowing continued telomerase activity and telomere elongation. By contrast, when telomeres were short, TRF2 was released from the telomeres and bound directly to the TERT promoter. There, together with a DNA structure called the G-quadruplex, TRF2 suppressed TERT expression and thereby limited further telomere extension. In other words, shortened telomeres repressed TERT expression, while elongated ones increased it. In this positive feedback–like reinforcement system, telomere length is signaled by the amount of free TRF2 protein. When TERT expression is high and telomeres are long, less TRF2 is available to bind the TERT promoter, reducing repression and thereby maintaining its expression. Conversely, when TERT expression is low and telomeres are short, more TRF2 is available, reinforcing repression and sustaining the low-expression state. Regulating telomere length is essential for healthy cell function, and its dysregulation is a hallmark of cancer. Sengupta et al. demonstrated that TRF2 plays a critical role in this process by feeding back information about telomere length directly to the TERT gene. By further dissecting this feedback system and refining experimental tools, researchers may gain new insights into telomere regulation in cancer and related diseases.
© 2025, Sengupta et al.