Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin

Nucleosome positioning varies between cell types. By deep sequencing cell-free DNA (cfDNA), isolated from circulating blood plasma, we generated maps of genome-wide in vivo nucleosome occupancy and found that short cfDNA fragments harbor footprints of transcription factors. The cfDNA nucleosome occupancies correlate well with the nuclear architecture, gene structure, and expression observed in cells, suggesting that they could inform the cell type of origin. Nucleosome spacing inferred from cfDNA in healthy individuals correlates most strongly with epigenetic features of lymphoid and myeloid cells, consistent with hematopoietic cell death as the normal source of cfDNA. We build on this observation to show how nucleosome footprints can be used to infer cell types contributing to cfDNA in pathological states such as cancer. Since this strategy does not rely on genetic differences to distinguish between contributing tissues, it may enable the noninvasive monitoring of a much broader set of clinical conditions than currently possible. [Display omitted] [Display omitted] •Sequencing cell-free DNA yields a genome-wide map of in vivo nucleosome occupancy•Short cell-free DNA fragments directly footprint transcription factor occupancy•In healthy persons, these epigenetic footprints match hematopoietic lineages•Additional contributions are detected in cancer, often aligning with the cancer type Deep sequencing of circulating cell-free DNA yields a dense, genome-wide map of nucleosome occupancy that enables identification of its cell-types of origin, potentially enabling the noninvasive monitoring of a much broader set of clinical conditions than currently possible.