{
  "abstract": "Dysregulation of three-dimensional (3D) genome architecture is a hallmark of cancer, yet the mechanisms by which its disruption drives tumorigenesis remain incompletely understood. Here, we demonstrated that SMAD4 regulated 3D genome organization through its canonical transcription factor activity by directly binding chromatin, thereby suppressing lung tumorigenesis. Hi-C analyses of human lung tumors identify SMAD4 as a potential regulator of 3D genome integrity. Using PTEN-deficient human bronchial epithelial cells and genetically engineered mouse models, we showed that SMAD4 loss induced widespread reorganization of chromatin compartments, topologically associating domain (TAD) boundaries, and chromatin loops, leading to oncogenic transcriptional rewiring during early tumorigenesis. Mechanistically, SMAD4 directly bound chromatin loops and spatially connected gene promoters with active or repressive regulatory elements to control transcription. Upon SMAD4 ablation, enhancer–promoter rewiring dysregulated critical oncogenic drivers, including ELF3. Functional manipulation of an SMAD4-regulated ELF3-associated chromatin loop altered ELF3 expression and cell survival both in vitro and in vivo. Collectively, our findings establish SMAD4 as a direct regulator of 3D genome architecture through classical transcription factor binding to chromatin loops and reveal enhancer–promoter rewiring as a key mechanism driving lung tumorigenesis and a potential therapeutic vulnerability in SMAD4-deficient lung cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China",
    "Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK",
    "ZJE Cross Lung Research Alliance, International Joint Center for Biomedical Sciences (Haining), Zhejiang University, Haining, China",
    "Department of Molecular Diagnostic Centre, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China",
    "Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China",
    "Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China",
    "First Affiliated Hospital of Zhejiang University, Hangzhou, China",
    "Department of Respiratory Diseases, Haining People’s Hospital, Haining, China",
    "Department of Pharmacy of the Second Affiliated Hospital of Zhejiang University School of Medicine, and ZJE, Zhejiang University, Hangzhou, China",
    "Department of Cardiology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China",
    "Department of Thoracic Surgery, Shenzhen Nanshan People’s Hospital, Shenzhen, China",
    "Department of Burns, the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China",
    "Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China",
    "Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, China",
    "Biomedical and Health Translational Research Center of Zhejiang Province, Haining, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 35,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yaping Xu",
      "orcid": "0009-0003-6621-0182"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Xinyan Han"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Junming Li",
      "orcid": "0009-0001-4940-9793"
    },
    {
      "affs": [
        3
      ],
      "name": "Shirong Zhang"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Chen Lian"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chenghang Yu"
    },
    {
      "affs": [
        4
      ],
      "name": "Zhanyu Xu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhenting Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Bo Yang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ran Ji"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Huiran Wang"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Manyu Xiao"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Zijin Wang",
      "orcid": "0009-0004-7856-3601"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Boyu Wang"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Silin Chen"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yunze Wang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yufei Liu"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Songsong Li"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zuolin Shen",
      "orcid": "0009-0000-7919-1417"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Xi Lu"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Xueqi Han"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Yilu Zhou"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yao Yao"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jiaqi Deng"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yijiang Guo"
    },
    {
      "affs": [
        5
      ],
      "name": "Lian Wang"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Shuifang Chen"
    },
    {
      "affs": [
        5
      ],
      "name": "Xiaoke Chen"
    },
    {
      "affs": [
        1,
        2,
        8
      ],
      "name": "Ying Chi",
      "orcid": "0000-0002-3020-7892"
    },
    {
      "affs": [
        1,
        2,
        8,
        9
      ],
      "name": "You Yu"
    },
    {
      "affs": [
        10
      ],
      "name": "Yong Tang",
      "orcid": "0000-0001-9478-5205"
    },
    {
      "affs": [
        1,
        8,
        11
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      "name": "Martin Kosar",
      "orcid": "0000-0002-9400-2327"
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    {
      "affs": [
        5
      ],
      "name": "Junqiang Fan"
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    {
      "affs": [
        4
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      "name": "Nuo Yang"
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    {
      "affs": [
        0,
        1,
        2,
        12,
        13,
        14
      ],
      "name": "Jian Liu",
      "orcid": "0000-0002-1447-0973"
    }
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  "bibtex": "https://research.draconitic.com/paper/3zyxr1c2ap28h.bib",
  "cited_by": 0,
  "doi": "10.1038/s41388-026-03984-6",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13713588/",
  "id": "3zyxr1c2ap28h",
  "issns": [
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    "1476-5594"
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  "landing_url": "https://doi.org/10.1038/s41388-026-03984-6",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
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  "pdf_url": "https://www.nature.com/articles/s41388-026-03984-6.pdf",
  "pmcid": "PMC13713588",
  "pmid": "42760353",
  "published": "2026-09-18",
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  "ris": "https://research.draconitic.com/paper/3zyxr1c2ap28h.ris",
  "sources": [
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    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
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  ],
  "title": "A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis",
  "title_text": "A canonical role of SMAD4 in safeguarding 3D genome architecture to suppress lung tumorigenesis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:14Z",
  "url": "https://research.draconitic.com/paper/3zyxr1c2ap28h",
  "venue": "Oncogene",
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}