Abstract High-resolution reconstruction of spatial chromosome organizations from chromatin contact maps is highly demanded, but is hindered by extensive pairwise constraints, substantial missing data, and limited resolution and cell-type availabilities. Here, we present FLAMINGO, a computational method that addresses these challenges by compressing inter-dependent Hi-C interactions to delineate the underlying low-rank structures in 3D space, based on the low-rank matrix completion technique. FLAMINGO successfully generates 5 kb- and 1 kb-resolution spatial conformations for all chromosomes in the human genome across multiple cell-types, the largest resources to date. Compared to other methods using various experimental metrics, FLAMINGO consistently demonstrates superior accuracy in recapitulating observed structures with raises in scalability by orders of magnitude. The reconstructed 3D structures efficiently facilitate discoveries of higher-order multi-way interactions, imply biological interpretations of long-range QTLs, reveal geometrical properties of chromatin, and provide high-resolution references to understand structural variabilities. Importantly, FLAMINGO achieves robust predictions against high rates of missing data and significantly boosts 3D structure resolutions. Moreover, FLAMINGO shows vigorous cross cell-type structure predictions that capture cell-type specific spatial configurations via integration of 1D epigenomic signals. FLAMINGO can be widely applied to large-scale chromatin contact maps and expand high-resolution spatial genome conformations for diverse cell-types.
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DiCARN-DNase: Enhancing Cell-to-Cell Hi-C Resolution Using Dilated Cascading ResNet with Self-Attention and DNase-seq Chromatin Accessibility Data
The spatial organization of chromatin is fundamental to gene regulation and essential for proper cellular function. The Hi-C technique remains the leading method for unraveling 3D genome structures, but the limited availability of high-resolution Hi-C data poses significant challenges for comprehensive analysis. Deep learning models have been developed to predict high-resolution Hi-C data from low-resolution counterparts. Early CNN-based models improved resolution but struggled with issues like blurring and capturing fine details. In contrast, GAN-based methods encountered difficulties in maintaining diversity and generalization. Additionally, most existing algorithms perform poorly in cross-cell line generalization, where a model trained on one cell type is used to enhance high-resolution data in another cell type. In this work, we propose DiCARN (Dilated Cascading Residual Network) to overcome these challenges and improve Hi-C data resolution. DiCARN leverages dilated convolutions and cascading residuals to capture a broader context while preserving fine-grained genomic interactions. Additionally, we incorporate DNase-seq data into our model, providing a robust framework that demonstrates superior generalizability across cell lines in high-resolution Hi-C data reconstruction. DiCARN is publicly available at https://github.com/OluwadareLab/DiCARN
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- Award ID(s):
- 2153205
- PAR ID:
- 10597660
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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