Fragmentation patterns of human telomeric chromatin in plasma cfDNA

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.