Telomere Position Effect Over Long Distance acts as a genome-wide epigenetic regulator through a commoncis- element

Among epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomere-dependent long-distance loops, with a reach of 10Mb from a telomere. However, TPE-OLD remains poorly defined. To gain further insights into the genome-wide impact of telomere length on genomic and epigenomic regulation through TPE-OLD, we used cells with controlled telomere length combined to a genome wide transcriptome and methylome analysis. By integrating omics data, we identified a common cis -acting motif that behaves as an insulator or enhancer. Using reporter assays integrating this element, we uncovered the trans partners regulating this activity. Further exploiting our cellular model, we observed the depletion of one candidate factor, RBPJ, at TPE-OLD associated loci upon telomere shortening. We concluded that, at the genome-wide level, TPE-OLD is relayed by RBPJ binding Alu-like elements to telomeres that acts as enhancers. In response to external stimuli ( i . e ., Aging), TPE-OLD might act by coordinating telomere length to the action of Alu newly evolved enhancers in association with RBPJ.