PSHIC reveals allele-specific chromatin organization by phasing-free structural modeling
Abstract
Resolving the distinct 3D chromatin architectures of parental chromosomes is critical for understanding diploid genome function, but many haplotype-resolved Hi-C contact-map methods remain constrained by their reliance on phased single-nucleotide polymorphisms (SNPs). This dependency treats reconstruction as a simple tag-and-sort problem, leading to massive data loss, extreme fragility to phasing errors, and inapplicability in SNP-sparse contexts. We introduce PSHIC, a computational framework that reveals this hidden chromatin organization by employing phasing-free structural modeling, directly from aggregated Hi-C data. PSHIC models chromosomes as continuous manifolds and solves the inverse problem of finding two homolog-specific structures whose combined contacts best explain the observed data. Comprehensive simulations across varying sequencing depths, SNP densities, and phasing error rates demonstrate that PSHIC consistently outperforms established methods, achieving superior accuracy (SCC ≥ 0.987), loop detection (F₁≥ 0.952), and structural fidelity (DER ≤ 0.04). Applications to real human and mouse Hi-C datasets show that PSHIC recovers known allele-associated features in X-chromosome inactivation, genomic imprinting, and regulatory networks. Results align with orthogonal experimental approaches including 3D DNA-FISH, 4C-seq, and ChIA-PET. PSHIC democratizes diploid chromatin analysis by enabling robust reconstruction in non-model organisms and other SNP-limited or poorly phased contexts.
Related
- Induction of hysteretic chromatin states by CRISPRa reveals locus-specific encoding of transcriptional memory
- Quantitative FLIM-FRET Microscopy to Monitor Nanoscale Chromatin Compaction In Vivo Reveals Structural Roles of Condensin Complexes
- Disentangling polymer confinement from specific-folding interactions reveals the drivers of Escherichia coli chromosome organization
- Uhrf1 loss disrupts CTCF-associated chromatin organization during early mouse embryogenesis
- Active Nucleosome Sliding, Eviction, and Reassembly Dynamics Can Regulate Chromatin Condensate Organization
BibTeX
@article{liu2026pshic,
title = {{PSHIC reveals allele-specific chromatin organization by phasing-free structural modeling}},
author = {Wei Liu and Xueying Wang and Yuwei Zhang and Guangze Pan and Shuaicheng LI},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78098-4},
url = {https://www.nature.com/articles/s41467-026-78098-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - PSHIC reveals allele-specific chromatin organization by phasing-free structural modeling
AU - Wei Liu
AU - Xueying Wang
AU - Yuwei Zhang
AU - Guangze Pan
AU - Shuaicheng LI
PY - 2026
DA - 2026/10/05
JO - Nature Communications
DO - 10.1038/s41467-026-78098-4
UR - https://www.nature.com/articles/s41467-026-78098-4
AB - Resolving the distinct 3D chromatin architectures of parental chromosomes is critical for understanding diploid genome function, but many haplotype-resolved Hi-C contact-map methods remain constrained by their reliance on phased single-nucleotide polymorphisms (SNPs). This dependency treats reconstruction as a simple tag-and-sort problem, leading to massive data loss, extreme fragility to phasing errors, and inapplicability in SNP-sparse contexts. We introduce PSHIC, a computational framework that reveals this hidden chromatin organization by employing phasing-free structural modeling, directly from aggregated Hi-C data. PSHIC models chromosomes as continuous manifolds and solves the inverse problem of finding two homolog-specific structures whose combined contacts best explain the observed data. Comprehensive simulations across varying sequencing depths, SNP densities, and phasing error rates demonstrate that PSHIC consistently outperforms established methods, achieving superior accuracy (SCC ≥ 0.987), loop detection (F₁≥ 0.952), and structural fidelity (DER ≤ 0.04). Applications to real human and mouse Hi-C datasets show that PSHIC recovers known allele-associated features in X-chromosome inactivation, genomic imprinting, and regulatory networks. Results align with orthogonal experimental approaches including 3D DNA-FISH, 4C-seq, and ChIA-PET. PSHIC democratizes diploid chromatin analysis by enabling robust reconstruction in non-model organisms and other SNP-limited or poorly phased contexts.
SN - 2041-1723
ER -