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

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