{
  "abstract": "Circulating cell-free DNA (cfDNA) fragmentation patterns reflect nucleosome positioning. We asked whether variation in nucleosome positions in cfDNA can reveal chromatin states and associated histone modifications. Using cell-free chromatin immunoprecipitation sequencing (cfChIP-seq) in plasma from patients with prostate cancer, we identified 35,120 modification-associated positions (MAPs), loci where nucleosomes bearing active (H3K4me2) and repressive (H3K9me3) histone marks occupy reproducibly offset positions. These offsets recurred across histone marks, an independent cfChIP-seq cohort, and nuclease-digested chromatin from cell lines. MAPs were enriched in transcribed genes but depleted near transcription start sites and CTCF-binding sites where nucleosome positioning is constrained. Across 2,535 cfDNA sequencing datasets, nucleosome protection at a subset of MAPs correlated with tumor fraction (TF), reflecting differences in histone modification status between cancer-derived and non-malignant chromatin. In targeted sequencing panels, a 50-MAP model using fragments from < 0.001% of the genome distinguished samples with tumor fractions [≥]3% vs 0% (AUCs = 0.91-0.96 across prostate, breast, and lung cancers) and outperformed a state-of-the-art fragmentomics-based tumor fraction predictor. MAP-derived estimates correlated with reference TFs (r = 0.89) and longitudinal changes in TF (r = 0.91). MAP protection at ASCL1 binding sites identified neuroendocrine transformation of prostate cancer from cfDNA. These findings establish histone-modification-associated nucleosome positioning as a mutation-independent readout of tumor fraction and cancer state from routine cfDNA sequencing.",
  "abstract_shown": true,
  "affiliations": [
    "Dana-Farber Cancer Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "name": "Y. Ou"
    },
    {
      "name": "G. S. Gulati"
    },
    {
      "name": "C. F. Tyndall"
    },
    {
      "name": "M. Pandey"
    },
    {
      "name": "J.-H. Seo"
    },
    {
      "name": "Z. Zhang"
    },
    {
      "name": "Z. Jin"
    },
    {
      "name": "G. G. Lee"
    },
    {
      "name": "R. Nawfal"
    },
    {
      "name": "T. A. Hoggood"
    },
    {
      "name": "S. D. Shahbazi"
    },
    {
      "name": "J. Ludwig"
    },
    {
      "name": "Z. Zhang"
    },
    {
      "name": "E. Ibrahim"
    },
    {
      "name": "G. Nafeh"
    },
    {
      "name": "J. E. Berchuck"
    },
    {
      "name": "A. G. Sowalsky"
    },
    {
      "name": "F. Karzai"
    },
    {
      "name": "M. L. Freedman"
    },
    {
      "name": "D. Y. Takeda"
    },
    {
      "affs": [
        0
      ],
      "name": "S. C. Baca"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0r2c80sptz05m.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.761423",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761423v1.full",
  "id": "0r2c80sptz05m",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761423v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ]
  ],
  "openalex": "W7224129233",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761423v1.full.pdf",
  "pmcid": "PMC13733833",
  "pmid": "42990193",
  "published": "2026-10-26",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/0r2c80sptz05m.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:08Z",
      "native_id": "10.64898/2026.10.26.761423",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761423v1"
    },
    {
      "first_seen": "2026-11-08T12:23:32Z",
      "native_id": "PMC13733833",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.26.761423"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Histone modifications define distinct nucleosome positions in cell-free DNA",
  "title_text": "Histone modifications define distinct nucleosome positions in cell-free DNA",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:32Z",
  "url": "https://research.draconitic.com/paper/0r2c80sptz05m",
  "venue": "bioRxiv",
  "versions": []
}