title: Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin.
abstract: 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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Snyder
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hill
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Riza M
authors.initials: RM
authors.lastname: Daza
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: shendure@uw.edu.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D000076246:CCCTC-Binding Factor; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018983:DNA Footprinting; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D009707:Nucleosomes / Q000737:chemistry*; D009928:Organ Specificity; D012097:Repressor Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D009707:Nucleosomes; D012097:Repressor Proteins; D004247:DNA