{
  "abstract": "Distinct PU.1 levels are associated with progenitor, B-cell, and macrophage states during hematopoietic differentiation. A previous dynamical-systems model attributed these levels to multistability generated by PU.1 autoregulation coupled to feedback between PU.1 abundance and cell-cycle progression, but its predictions were not quantitatively evaluated against the motivating measurements. Here, we test this mechanism using reported measurements of PU.1 abundance, its synthesis rate, and cell-cycle duration, and develop progressively more mechanistic alternatives. The original growth-feedback model neither represents the two reported progenitor groups nor reproduces the nonmonotonic relationship between PU.1 abundance and cell-cycle length. Even with experimentally measured cell-type-specific growth rates, PU.1 autoregulation alone does not reproduce the observed PU.1 abundance and synthesis rates across cell states. Reproducing the cell-state measurements requires an additional cell-state-dependent input to PU.1 production. Guided by enhancer regulation, we model positive feedback between PU.1 and C/EBP and constrain it with reporter measurements, but this architecture cannot jointly reproduce the reporter and cell-state datasets. Adding RUNX1 permits data-consistent stable states when high effective cooperativity in PU.1-dependent C/EBP activation is allowed. Thus, combined dynamical and cis-regulatory constraints support additional regulation of PU.1 production beyond autoregulation, cell-type-specific dilution, and C/EBP feedback. The RUNX1-extended architecture provides one biologically grounded realization and generates experimentally testable hypotheses for differentiation networks.",
  "abstract_shown": true,
  "affiliations": [
    "Rice University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "O. A. Igoshin"
    },
    {
      "name": "Y. Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2d3bzw4nemdqc.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.01.756127",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1.full",
  "id": "2d3bzw4nemdqc",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Gene Regulatory Network Analysis"
    ]
  ],
  "openalex": "W7219737488",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2d3bzw4nemdqc.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:57Z",
      "native_id": "10.64898/2026.10.01.756127",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756127v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Integrating cell-state and enhancer constraints discriminates models of PU.1 regulation during hematopoietic differentiation",
  "title_text": "Integrating cell-state and enhancer constraints discriminates models of PU.1 regulation during hematopoietic differentiation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:57Z",
  "url": "https://research.draconitic.com/paper/2d3bzw4nemdqc",
  "venue": "bioRxiv",
  "versions": []
}