RT Journal Article SR Electronic T1 Ultra-long-range interactions between active regulatory elements JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.11.30.518557 DO 10.1101/2022.11.30.518557 A1 Elias T. Friman A1 Ilya M. Flyamer A1 Shelagh Boyle A1 Wendy A. Bickmore YR 2022 UL http://biorxiv.org/content/early/2022/11/30/2022.11.30.518557.abstract AB Contacts between enhancers and promoters are thought to relate to their ability to activate transcription. Investigating mechanisms that drive such chromatin interactions is therefore important for understanding gene regulation. Here, we have determined contact frequencies between millions of pairs of cis-regulatory elements from chromosome conformation capture datasets and analysed a collection of hundreds of DNA-binding factors for binding at regions of enriched contacts. This analysis revealed enriched contacts at sites bound by many factors associated with active transcription. We show that active regulatory elements, independent of cohesin and polycomb, interact with each other across distances of 10s of megabases in vertebrate and invertebrate genomes and that interactions correlate and change with activity. However, these ultra-long-range interactions are not dependent on RNA polymerase II transcription or several transcription cofactors. We propose that long-range interactions between cis-regulatory elements are driven by three distinct mechanisms – cohesin-mediated loop extrusion, polycomb contacts, and association between active regions.Competing Interest StatementThe authors have declared no competing interest.