Abstract
Recent genome-wide chromosome conformation capture assays such as Hi-C and HiChIP have vastly expanded the resolution and throughput with which we can study 3D genomic architecture and function. Here, we present HiC-DC+, a software tool for Hi-C/HiChIP interaction calling and differential analysis using an efficient implementation of the HiC-DC statistical framework. HiC-DC+ integrates with popular preprocessing and visualization tools and includes topologically associating domain (TAD) and A/B compartment callers. We found that HiC-DC+ can more accurately identify enhancer-promoter interactions in H3K27ac HiChIP, as validated by CRISPRi-FlowFISH experiments, compared to existing methods. Differential HiC-DC+ analyses of published HiChIP and Hi-C data sets in settings of cellular differentiation and cohesin perturbation systematically and quantitatively recovers biological findings, including enhancer hubs, TAD aggregation, and the relationship between promoter-enhancer loop dynamics and gene expression changes. HiC-DC+ therefore provides a principled statistical analysis tool to empower genome-wide studies of 3D chromatin architecture and function.
Highlights
Recent genome-wide chromosome conformation capture assays such as Hi-C and HiChIP have vastly expanded the resolution and throughput with which we can study 3D genomic architecture and function
Similar to HiC-DC9, HiC-DC+ uses negative binomial (NB) regression to estimate the expected read count in an interaction bin based on genomic distance and the GC content, mappability, and effective bin size based on restriction enzyme (RE) sites in the corresponding pair of genomic intervals (Methods); genomic features derived from the set of RE recognition sites are provided as input to the model
We have shown that HiC-DC+ facilitates genome-wide analyses of Hi-C and HiChIP data sets and integration with 1D epigenomic and transcriptomic data, recovering previous biological findings in a systematic and global fashion while enabling new insights on the role of 3D genomic architecture in gene regulation
Summary
Recent genome-wide chromosome conformation capture assays such as Hi-C and HiChIP have vastly expanded the resolution and throughput with which we can study 3D genomic architecture and function. HiChIP4 couples Hi-C with chromatin immunoprecipitation for a protein or histone mark of interest, and capture Hi-C5 uses an oligonucleotide probe library to enrich for interactions with specific loci These advances in technology make possible the generation of high-resolution interaction data sets in multiple cell types, together with biological replicates, for studying changes in genomic architecture with cellular context and how 3D interaction changes are related to epigenomic and transcriptional changes. HiC-DC+ instead identifies widespread differential enhancer–promoter interactions that are associated with concordant gain or loss of H3K27ac-marked accessible elements and gene expression changes Together, these analyses demonstrate the power of HiC-DC+ for systematic global analysis of 3D genomic interactions, including regulatory interactions, and biological interpretation
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