The structure and dynamics of the eukaryotic genome are intimately linked to gene regulation and transcriptional activity. Many chromosome conformation capture experiments like Hi-C have been developed to detect genome-wide contact frequencies and quantify loop/compartment structures for different cellular contexts and time-dependent processes. However, a full understanding of these events requires explicit descriptions of representative chromatin and chromosome configurations. With the exponentially growing amount of data from Hi-C experiments, many methods for deriving 3D structures from contact frequency data have been developed. Yet, most reconstruction methods use polymer models with low resolution to predict overall genome structure. Here we present a Brownian Dynamics (BD) approach termed Hi-BDiSCO for producing 3D genome structures from Hi-C and Micro-C data using our mesoscale-resolution chromatin model based on the Discrete Surface Charge Optimization (DiSCO) model. Our approach integrates reconstruction with chromatin simulations at nucleosome resolution with appropriate biophysical parameters. Following a description of our protocol, we present applications to the NXN, HOXC, HOXA and Fbn2 mouse genes ranging in size from 50 to 100 kb. Such nucleosome-resolution genome structures pave the way for pursuing many biomedical applications related to the epigenomic regulation of chromatin and control of human disease.
High throughput chromosome conformation capture (Hi-C) contact matrices are used to predict 3D chromatin structures in eukaryotic cells. High-resolution Hi-C data are less available than low-resolution Hi-C data due to sequencing costs but provide greater insight into the intricate details of 3D chromatin structures such as enhancer–promoter interactions and sub-domains. To provide a cost-effective solution to high-resolution Hi-C data collection, deep learning models are used to predict high-resolution Hi-C matrices from existing low-resolution matrices across multiple cell types.
Here, we present two Cascading Residual Networks called HiCARN-1 and HiCARN-2, a convolutional neural network and a generative adversarial network, that use a novel framework of cascading connections throughout the network for Hi-C contact matrix prediction from low-resolution data. Shown by image evaluation and Hi-C reproducibility metrics, both HiCARN models, overall, outperform state-of-the-art Hi-C resolution enhancement algorithms in predictive accuracy for both human and mouse 1/16, 1/32, 1/64 and 1/100 downsampled high-resolution Hi-C data. Also, validation by extracting topologically associating domains, chromosome 3D structure and chromatin loop predictions from the enhanced data shows that HiCARN can proficiently reconstruct biologically significant regions.
HiCARN can be accessed and utilized as an open-sourced software at: https://github.com/OluwadareLab/HiCARN and is also available as a containerized application that can be run on any platform.
Supplementary data are available at Bioinformatics online.
- NSF-PAR ID:
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Medium: X Size: p. 2414-2421
- ["p. 2414-2421"]
- Sponsoring Org:
- National Science Foundation
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Availability and implementation
The source code and user manual: https://github.com/jianlin-cheng/GenomeFlow.
Supplementary data are available at Bioinformatics online.