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

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, influence regulation is relatively less studied. We found was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the promoter. promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to the 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 , respectively. Mechanistically, we show 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 reporter. Increase in TL over days followed by a gradual decline, resulted in activation followed by repression of in a concerted manner, further implicating TL as a key factor for regulation. Notably, on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from the promoter was evident along with telomere elongation and upregulation. Conversely, on telomere shortening in iPSCs, promoter-bound TRF2 was restored with a marked reduction in further supporting the causal role of TL in transcription. Mechanisms of tight control of by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency.