title: Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin.
abstract: Discriminating the gene target of a distal regulatory element from other nearby transcribed genes is a challenging problem with the potential to illuminate the causal underpinnings of complex diseases. We present TargetFinder, a computational method that reconstructs regulatory landscapes from diverse features along the genome. The resulting models accurately predict individual enhancer-promoter interactions across multiple cell lines with a false discovery rate up to 15 times smaller than that obtained using the closest gene. By evaluating the genomic features driving this accuracy, we uncover interactions between structural proteins, transcription factors, epigenetic modifications, and transcription that together distinguish interacting from non-interacting enhancer-promoter pairs. Most of this signature is not proximal to the enhancers and promoters but instead decorates the looping DNA. We conclude that complex but consistent combinations of marks on the one-dimensional genome encode the three-dimensional structure of fine-scale regulatory interactions.
authors.affiliation: Gladstone Institutes, San Francisco, California, USA.|Division of Biostatistics, Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.|Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Whalen
authors.affiliation: Invitae Corporation, San Francisco, California, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Truty
authors.affiliation: Gladstone Institutes, San Francisco, California, USA.|Division of Biostatistics, Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.|Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
mesh_terms: D000465:Algorithms; D002460:Cell Line; D002843:Chromatin; D004247:DNA; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation
chemical_list: D002843:Chromatin; D004247:DNA