{
  "abstract": "Three-dimensional (3D) chromosome reconstruction from Hi-C contact maps remains challenging because genome organization is hierarchical and fine-resolution models must reconcile local structure with chromosome-scale constraints. Here we present HiC-LEGO, a domain-aware hierarchical framework integrating ensemble chromatin domains with graph-based structural learning and progressive chromosome assembly. By combining ensemble domain selection with hierarchical reconstruction, HiC-LEGO reduces dependence on individual domain definitions while maintaining local organization during chromosome-scale assembly. Across five human cell lines at 5-kb resolution, HiC-LEGO achieves higher reconstruction concordance than evaluated state-of-the-art methods while better preserving domain organization. At 1-kb resolution, HiC-LEGO reconstructs complete GM12878 chromosome 8 and recovers close spatial proximity between an epigenomically supported distal MYC enhancer and its promoter. Reconstructions from 5-kb Micro-C data show that 249 experimentally defined RCMC microcompartment interactions at the Ppm1g locus occupy compact 3D configurations. In the breast cancer dataset, HiC-LEGO reconstructs structures that maintain stable TAD organization across healthy breast, primary tumors, and liver metastases, while revealing greater inter-patient structural heterogeneity in malignant pleural effusion samples. Pore-C validation shows that experimentally observed multi-way contacts spanning 1-5 Mb are enriched in compact reconstructed configurations across all 23 chromosomes. Thus, HiC-LEGO preserves regulatory interactions, disease-associated chromatin organization and higher-order spatial relationships beyond pairwise contact-map concordance.",
  "abstract_shown": true,
  "affiliations": [
    "University of North Texas (Denton, TX)"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "A. Pandeya"
    },
    {
      "name": "M. F. K. Chowdhury"
    },
    {
      "affs": [
        0
      ],
      "name": "O. Oluwadare"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3fvnk0br7897g.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.30.748130",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1.full",
  "id": "3fvnk0br7897g",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1",
  "language": null,
  "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",
      "bioinformatics"
    ],
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ]
  ],
  "openalex": "W7208736489",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3fvnk0br7897g.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:19Z",
      "native_id": "10.64898/2026.08.30.748130",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "HiC-LEGO: Biologically Guided High-Resolution 3D Genome Reconstruction Preserves Chromatin Organization at Kilobase Resolution",
  "title_text": "HiC-LEGO: Biologically Guided High-Resolution 3D Genome Reconstruction Preserves Chromatin Organization at Kilobase Resolution",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:19Z",
  "url": "https://research.draconitic.com/paper/3fvnk0br7897g",
  "venue": "bioRxiv",
  "versions": []
}