Fragmentation Patterns of Human Telomeric Chromatin in Plasma cfDNA

ABSTRACT: The unique chromatin structure at telomeres protects the ends of our chromosomes from being recognized as DNA damage and preserves genome integrity by preventing recombination. Here, we demonstrate that circulating cell-free DNA (cfDNA) from plasma can be used to map chromatin structure at telomeres. Using an alignment-free approach to overcome challenges in characterizing repetitive regions of DNA using sequencing, 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. To map nucleosomal footprints from telomeric sequences in cfDNA, we performed long-read sequencing. We identified a nucleosome repeat length of 145 bp for telomeric sequences, which is significantly shorter than the repeat length of ~170 bp for the rest of the genome. The abundance of cfDNA telomeric footprints decreases with age, and this decline is exacerbated by Dyskeratosis Congenita (DC), a telomere biology disorder. DC also alters subtelomeric chromatin accessibility, as determined from cfDNA, allowing us to capture genome-wide effects of shortened telomeres non-invasively. Promoter subnucleosome enrichment (PSE) from cfDNA identifies DC-specific gene signatures that reflect disease states observed in transcriptomic studies. Notably, DC-specific gene signatures correlate with decreased cfDNA telomere footprint abundance and show enrichment of genes towards the ends of chromosomes. In summary, cfDNA provides an unexpected means to map telomere chromatin state and the impact of telomere shortening on the rest of the genome, offering a non-invasive way to track gene expression changes in DC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305882 | GEO | 2026/07/17

REPOSITORIES: GEO