Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions
Hangpeng Li, James Dalgleish, George Lister, Maria Julia Maristany, Jan Huertas, Ana M. Dopico-Fernandez, Joseph C. Hamley, Nicholas Denny, Gianna Bloye, Weijiao Zhang, Lance D. Hentges, Roman Doll, Ye Wei, Michela Maresca, Emilia Dimitrova, Lior Pytowski, Edward Tunnacliffe, Mira Kassouf, Douglas R. Higgs, Elzo de Wit, Robert J. Klose, Lothar Schermelleh, Rosana Collepardo‐Guevara, Thomas A. Milne, James Davies
Abstract
Chromatin structure is a key determinant of gene expression in eukaryotes, but it has not been possible to define the structure of cis-regulatory elements at the scale of the proteins that bind them. Here, we generate multidimensional chromosome conformation capture (3C) maps at base-pair resolution using Micro Capture-C ultra (MCCu). This can resolve contacts between individual transcription factor motifs within cis-regulatory elements. Using degron systems, we show that removal of Mediator complex components alters fine-scale promoter structure and that nucleosome depletion plays a key role in transcription factor-driven enhancer-promoter contacts. We observe that chromatin is partitioned into nanoscale domains by nucleosome-depleted regions. This structural conformation is reproduced by chemically specific coarse-grained molecular dynamics simulations of the physicochemical properties of chromatin. Combining MCCu with molecular dynamics simulations and super-resolution microscopy allows us to propose a unified model in which the biophysical properties of chromatin orchestrate contacts between cis-regulatory elements.