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Telomere Position Effect‐Over Long Distances Acts as a Genome‐Wide Epigenetic Regulator Through a Common Alu Element
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Telomere Position Effect‐Over Long Distances Acts as a Genome‐Wide Epigenetic Regulator Through a Common Alu Element
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Telomere Position Effect‐Over Long Distances Acts as a Genome‐Wide Epigenetic Regulator Through a Common Alu Element
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Journal Article
Telomere Position Effect‐Over Long Distances Acts as a Genome‐Wide Epigenetic Regulator Through a Common Alu Element
2025
Overview
Among epigenetic modifiers, telomeres represent attractive modulators of the genome in part through position effects. Telomere Position Effect‐Over Long Distances (TPE‐OLD) modulates gene expression by changes in telomere‐dependent long‐distance loops. To gain insights into the molecular mechanisms of TPE‐OLD, we performed a genome‐wide transcriptome and methylome analysis in proliferative fibroblasts and myoblasts or differentiated myotubes with controlled telomere lengths. By integrating omics data, we identified a common TPE‐OLD dependent cis‐acting motif that behaves as an insulator or enhancer. Next, we uncovered trans partners that regulate these activities and observed the consistent depletion of one candidate factor, RBPJ, at TPE‐OLD associated loci upon telomere shortening. Importantly, we confirmed our findings by unbiased comparisons to recent Human transcriptomic studies, including those from the Genotype‐Tissue Expression (GTEx) project. We concluded that TPE‐OLD acts at the genome‐wide level and can be relayed by RBPJ bridging Alu‐like elements to telomeres. In response to physiological (i.e., aging) or pathological cues, TPE‐OLD might coordinate the genome‐wide impact of telomeres through recently evolved Alu elements acting as enhancers in association with RBPJ. Proposed TPE‐OLD model. TPE‐OLD genes are defined by a progressive modulation of gene expression following telomere attrition. In our study, focusing on the molecular mechanism of TPE‐OLD, we found that the TPE‐OLD loop requires a cis‐signature corresponding to a newly evolved Alu repeats (AluY). The Alu repeat can be either in an intergenic region, as the sequence holds the same properties as an enhancer/insulator, or positioned within the gene, thus potentially affecting splicing. The DNA‐loop is maintained by trans partners, including SMCHD1, TZAP, TRF2, and more specifically RBPJ. As telomere shortens and DNA methylation associated with the Alu element decreases, the distance between the TPE‐OLD gene and telomeres increases and induces a modulation of transcription. We conclude that TPE‐OLD is regulated at three levels: (i) at the telomere through its associated length, (ii) at the Alu element through its associated methylation, and (iii) at the telomere‐associated proteins levels and their localization (SMCHD1, TZAP, TRF2, RBPJ). According to our work, RBPJ (directly or indirectly) along with TRF2 (directly) are the most important proteins for the maintenance of the TPE‐OLD loop.
