Protein binding and methylation on looping chromatin accurately predict distal regulatory interactions

Identifying the gene targets of distal regulatory sequences is a challenging problem with the potential to illuminate the causal underpinnings of complex diseases. However, current experimental methods to map enhancer-promoter interactions genome-wide are limited by their cost and complexity. We present TargetFinder, a computational method that reconstructs a cells three-dimensional regulatory landscape from two-dimensional genomic features. TargetFinder achieves outstanding predictive accuracy across diverse cell lines with a false discovery rate up to fifteen times smaller than common heuristics, and reveals that distal regulatory interactions are characterized by distinct signatures of protein interactions and epigenetic marks on the DNA loop between an active enhancer and targeted promoter. Much of this signature is shared across cell types, shedding light on the role of chromatin organization in gene regulation and establishing TargetFinder as a method to accurately map long-range regulatory interactions using a small number of easily acquired datasets.