Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions

HP Li and JLT Dalgleish and G Lister and MJ Maristany and J Huertas and AM Dopico-Fernandez and JC Hamley and N Denny and G Bloye and WJ Zhang and L Hentges and R Doll and Y Wei and M Maresca and E Dimitrova and L Pytowski and EAJ Tunnacliffe and M Kassouf and D Higgs and E De Wit and RJ Klose and L Schermelleh and R Collepardo-Guevara and TA Milne and JOJ Davies, CELL, 188, 7175-7193 (2025).

DOI: 10.1016/j.cell.2025.10.013

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.

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