Abstract
Proximity-ligation methods such as Hi-C allow us to map physical DNA–DNA interactions along the genome, and reveal its organization into topologically associating domains (TADs). As the Hi-C data accumulate, computational methods were developed for identifying domain borders in multiple cell types and organisms. Here, we present PSYCHIC, a computational approach for analyzing Hi-C data and identifying promoter–enhancer interactions. We use a unified probabilistic model to segment the genome into domains, which we then merge hierarchically and fit using a local background model, allowing us to identify over-represented DNA–DNA interactions across the genome. By analyzing the published Hi-C data sets in human and mouse, we identify hundreds of thousands of putative enhancers and their target genes, and compile an extensive genome-wide catalog of gene regulation in human and mouse. As we show, our predictions are highly enriched for ChIP-seq and DNA accessibility data, evolutionary conservation, eQTLs and other DNA–DNA interaction data.
Highlights
Background modelHi-C (FDR
Hi-C interaction maps often show a clear distinction between two different patterns—Rectangular regions along the diagonal of the Hi-C map that correspond to topological domains, and present high intensity of DNA–DNA interactions
Hi-C maps are often rotated in 45 degrees, with topological domains shown as isosceles right triangles along the diagonal of the Hi-C map (Fig. 1a)
Summary
Ground-truth data for promoter–enhancer interactions are still limited, and we have taken multiple approaches to establish our predictions. We showed that the predicted enhancer regions are enriched for active marks (H3K27ac, H3K4me[1], PolII), DNA accessibility, or CTCF. This was shown initially for a single locus (Foxg1) in the mouse cortex, and later supported in a genomewide manner over multiple tissues. We used high-throughput eQTL data, linking genotypes and gene expression profiles in hundreds of donors, and intersected them with our predictions. We used recently published cryo-sections of nuclei, showing that predicted promoter–enhancer pairs are co-sliced more often expected
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