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

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.

Keywords: chromatin structure; chromosome conformation capture; cis-regulatory elements; enhancer-promoter interactions; gene regulation; mediator complex; molecular dynamics simulations; nuclear organization; transcription factors.

Summary

This article explains a new way to map how DNA is folded and controlled inside cells.

The researchers found that small DNA control areas form detailed local shapes. They also showed that some proteins help keep these shapes in place and support contact between genes and nearby control regions.

Keywords: DNA structure, gene control regions, gene contacts, open DNA areas, control proteins, Mediator protein group, CTCF, DNA loops, Micro Capture-C ultra, tiny DNA regions, computer modelling, powerful microscopy