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

The function of the human telomerase reverse transcriptase (hTERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influencehTERTregulation is relatively less studied. We foundhTERTwas transcriptionally up/downregulated depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and thehTERTpromoter.hTERTpromoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to thehTERTpromoter. Cell lines from different tissue types (fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening gave increase/decrease inhTERT, respectively. Mechanistically, we showhTERTpromoter-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 insertedhTERTreporter. Increase in TL over days followed by gradual decline, resulted in activation followed by repression ofhTERTin a concerted manner, further implicating TL as a key factor forhTERTregulation. Notably on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from thehTERTpromoter was evident along with telomere elongation andhTERTupregulation. Conversely, on telomere shortening in iPSCs,hTERTpromoter-bound TRF2 was restored with marked reduction inhTERTfurther supporting the causal role of TL inhTERTtranscription. Mechanisms of tight control ofhTERTby TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing and pluripotency.