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

2025/11/05 by Hangpeng Li, James Dalgleish, George Lister +22 · 1 voice · 8 citations
Biochemistry, Genetics and Molecular Biology · #Genomics and Chromatin Dynamics #DNA and Nucleic Acid Chemistry #Developmental Biology and Gene Regulation

paper · doi:10.1016/j.cell.2025.10.013

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.

Citations

• Pioneer Transcription Factors Initiating Gene Network Changes
• Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization
• Fast Parallel Algorithms for Short-Range Molecular Dynamics

Cited by

• FACT safeguards promoter topology by maintaining nucleosomes and restricting chromatin factor spreading
• Nucleotide resolution 4-thiouridine sequencing by SNU-Seq and sf4sU-Seq reveals the transcriptional responsiveness of an epigenetically primed human genome
• Chromosome conformation capture [wikipedia]
• Artificial intelligence virtual extracellular vesicles (AIVEVs). [europepmc]
• Architecture and regulation of nanoscale chromatin domains. [europepmc]
• Resolving Sub-Nuclear Architecture from Compartments to Functional Domains. [europepmc]
• Self-organization of Drosophila chromatin architecture in a cell-free system [europepmc]
• FACT safeguards promoter topology by maintaining nucleosomes and restricting chromatin factor spreading [europepmc]

Discussions

• Our latest paper has just been published in Cell! doi.org/10.1016/j.ce... We developed a new method called MCC ultra, which allows 3D chromatin structure to be visualised with a 1 base pair pixel si [bsky, 209 points, 6 comments]

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