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Fragmentation Patterns of Human Telomeric Chromatin in Plasma cfDNA

Buck, B.; Weirich, A.; Eramo, S.; Lopez, R.; White, L. K.; Kabos, P.; Forester, C.; Ramachandran, S.

2026-05-30 genomics
10.64898/2026.05.28.728442 bioRxiv
Show abstract

The unique chromatin structure at telomeres protects the linear ends of chromosomes from DNA surveillance machineries. Here, we demonstrate that circulating cell-free DNA (cfDNA) from plasma can map chromatin structure at telomeres. We find that the telomeric 6-mer repeats (TTAGGG/CCCTAA) are the most abundant circulating 6-mers in cfDNA. Telomeric sequences in cfDNA contain subnucleosomal footprints distinct from the rest of the genome, arising from specific cleavages in the C-rich strand, and a nucleosome repeat length of 145 bp, markedly shorter than the [~]170 bp observed genome-wide. The abundance of cfDNA telomeric footprints decreases with age, and this decline is exacerbated by Dyskeratosis Congenita (DC), a telomere biology disorder. Promoter subnucleosome enrichment from cfDNA identifies DC-specific gene signatures that reflect disease states and show enrichment towards chromosome ends. In this work, we demonstrate that cfDNA captures telomere chromatin structure and its genome-wide impact non-invasively, including disease-specific signatures in DC.

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