EPAS1 protects fibroblasts from replicative senescence through telomeric stability

Telomeres are nucleoprotein structures at the end of each chromosome and function to terminal protection and genomic stability maintenance. Telomeric damage and attrition is closely related to cell division disability and replicative senescence in vitro, as well as to physical aging in vivo. Exploration of valuable targets of enhancing telomeric stability and delaying the entry of senescence could benefit human health. Our study stemmed from the observation that bat (Rhinolophus sinicus) fibroblasts exhibited super abilities of telomeric protection and were much resistant to replicative senescence, compared to counterparts from mouse and human. With mRNA sequencing and overlapping analysis with TelNet database (http://www.cancertelsys.org/telnet/), we identified EPAS1, which is a well-studied oxygen response gene, as a novel telomeric protector. Bat fibroblasts kept high-level expression of EPAS1. EPAS1 directly promoted the transcription of telomeric genes TRF1, TRF2 and RAD50, and avoided telomeric attrition. We further confirmed that EPAS1 agonist M1001 stabilized telomeres and postponed senescence accumulation in major organs of mice in vivo. In summary, these results indicate that activating EPAS1 might be a valuable avenue towards extension of human health span.