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  • High-Resolution Long-Read Telomere Sequencing Explores Aging and Cancer Mechanisms

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    Telomeres (green) protect the ends of our chromosomes (blue), but lose this protective capacity as we age. (Image Credit: Salk Institute)



    A recent study published in Nature Communications presents an advanced sequencing method called Telo-seq, which offers unprecedented insights into telomere biology, particularly in the contexts of aging and cancer. This study was a collaborative effort between researchers from the Salk Institute for Biological Studies, Oxford Nanopore Technologies, and the University of California, San Diego.

    A Novel Approach to Telomere Analysis
    Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play a crucial role in protecting chromosome ends from degradation. However, their repetitive nature and considerable length have historically complicated precise measurements of individual telomere lengths. Telo-seq, leveraging Oxford Nanopore Technologies' native long-read sequencing, addresses these challenges by resolving telomere lengths at the bulk, chromosome arm-specific, and allele-specific levels.

    The method involves annealing telorette-based telomere adapters to the telomere overhang, followed by genomic DNA digestion with EcoRV. Sequencing adapters are then ligated, and the DNA is subjected to long-read sequencing. This approach enables accurate mapping of telomeric reads to specific chromosome arms, providing detailed insights into telomere composition and length.

    Telomere Length Heterogeneity
    Using the B-lymphocyte cell line HG002, the researchers demonstrated that Telo-seq could significantly enhance telomeric read coverage compared to traditional methods. They observed notable heterogeneity in telomere lengths between different chromosome arms, with some arms exhibiting much longer or shorter telomeres than others. This heterogeneity persisted even within individual cells, indicating that telomere length variability is a common feature.

    Telomere Dynamics in Aging and Cancer
    To explore telomere shortening dynamics, the team analyzed IMR90 human lung fibroblasts expressing human papillomavirus oncogenes. The results showed progressive telomere shortening with increasing population doublings, a finding consistent with the end-replication problem and subsequent cellular processing. The study estimated that telomeres shorten by approximately 39 base pairs per population doubling under the specified growth conditions.

    In the context of cancer, Telo-seq successfully differentiated between telomerase (TERT)-positive and alternative lengthening of telomeres (ALT)-positive cancer cell lines. The ALT-positive cells displayed a broader and more heterogeneous telomere length distribution compared to TERT-positive cells, suggesting that Telo-seq can be a valuable tool in identifying telomere maintenance mechanisms in various cancers.

    Telomere Length in Aging
    The researchers also applied Telo-seq to fibroblasts derived from human donors aged 20 to 94 years. They found that telomeres were generally shorter in older individuals, with significant intrasample heterogeneity in telomere lengths across different chromosome arms. Interestingly, one 82-year-old donor exhibited telomere lengths comparable to those of much younger individuals, highlighting the complex relationship between aging and telomere dynamics.

    Conclusion
    Telo-seq represents a significant advancement in the field of telomere biology, offering a robust and detailed method for analyzing telomere length and composition. By providing high-resolution insights into telomere dynamics, Telo-seq can aid in understanding the mechanisms underlying aging and cancer, paving the way for potential therapeutic interventions targeting telomere maintenance mechanisms.

    Publication Details
    Schmidt, T.T., Tyer, C., Rughani, P. et al. High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer. Nat Commun 15, 5149 (2024). https://doi.org/10.1038/s41467-024-48917-7

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