CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps

Spatiotemporal gene expression patterns are governed to a large extent by enhancer elements, typically located distally from their target genes. Identification of enhancer-promoter (EP) links that are specific and functional in individual cell types is a key challenge in understanding gene regulation. We introduce CT-FOCS, a new statistical inference method that utilizes multiple replicates per cell type to infer cell type-specific EP links. Computationally predicted EP links are usually benchmarked against experimentally determined chromatin interaction measured by ChIA-PET. We expand this validation scheme by introducing the concept of connected loop set, which combines loops that overlap in their anchor sites. Analzying 1,366 samples from ENCODE, Roadmap epigenomics and FANTOM5, CT-FOCS inferred highly cell type-specific EP links more accurately than a state-of-the-art method. We illustrate how our inferred EP links drive cell type-specific gene expression and regulation.