Telomeres control regulation of the human Telomerase (hTERT) gene through non-telomeric TRF2 and independent of Telomere looping

Abstract

AbstractActivation of human telomerase (hTERT) and resulting maintenance of telomeres is widely understood. Whether telomeres, on the other hand, influencehTERTregulation is relatively less studied. We foundhTERTwas transcriptionally up/down regulated depending on telomere length (TL), but independent of telomere looping. Cells from different tissues, engineered for either telomere elongation/shortening gave increase/decrease inhTERT, respectively. Temporal increase of TL, followed by decrease over days, resulted in induction and subsequent repression ofhTERT, supporting the causal role of TL. Further confirmed by TL-dependent promoter activity from exogenously insertedhTERTreporter. Mechanistically, we show non-telomeric TRF2 binding at thehTERTpromoter to be TL-dependent. Promoter bound TRF2 recruited the canonical PRC2-complex inducing repressor histone H3K27-trimethylation. Together, these reveal a heretofore unaddressed model of telomere homeostasis in telomerase-positive cells, where TL-dependenthTERTlevels in turn maintain long/short telomeres. This might help better understand telomere-related physiologies like cancer, ageing and pluripotency.