HiC-LEGO: Biologically Guided High-Resolution 3D Genome Reconstruction Preserves Chromatin Organization at Kilobase Resolution
- 1University of North Texas (Denton, TX)
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.
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BibTeX
@misc{pandeya2026hiclego,
title = {{HiC-LEGO: Biologically Guided High-Resolution 3D Genome Reconstruction Preserves Chromatin Organization at Kilobase Resolution}},
author = {A. Pandeya and M. F. K. Chowdhury and O. Oluwadare},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.748130},
url = {https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - HiC-LEGO: Biologically Guided High-Resolution 3D Genome Reconstruction Preserves Chromatin Organization at Kilobase Resolution
AU - A. Pandeya
AU - M. F. K. Chowdhury
AU - O. Oluwadare
PY - 2026
DA - 2026/08/30
PB - bioRxiv
DO - 10.64898/2026.08.30.748130
UR - https://www.biorxiv.org/content/10.64898/2026.08.30.748130v1
AB - 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.
ER -