Genome-wide enhancer – gene regulatory maps in two vertebrate genomes

Gene regulation by enhancer sequences controls the spatiotemporal expression of target genes, often over long genomic distances. Current methods used to identify these interactions in the human genome require complex experimental setups and are restricted to specific cell types. Here we use PEGASUS, an approach that captures evolutionary signals of synteny conservation to predict such interaction potentially in any biological context. We apply it to the human and zebrafish genomes and exploit the 1.3 million human and 55,000 zebrafish enhancers that we predicted to uncover fundamental principles of gene enhancer function in vertebrates. We show that the number of enhancers linked to a gene positively correlates with expression breadth in space and time and that the enhancer-target distance is evolutionarily neutral. We uncover almost 2000 regulatory interactions ancestral to vertebrates, which are strongly enriched in core developmental processes. Using PEGASUS and its evolutionary view of enhancer-gene interactions, we provide a highly complementary resource to functional assays which uncovers key principles of enhancer biology.