以碱基对分辨率绘制染色质结构揭示了顺式调控元件相互作用的统一模型，这一成果由牛津大学James O.J. Davies研究团队经过不懈努力而取得。该研究于2025年11月5日发表于国际一流学术期刊《细胞》杂志上。
该课题组以碱基对分辨率为主题的Micro Capture-C ultra（MCCu）生成了多维染色体构象捕获（3C）图。这可以解决在顺式调控元件中单个转录因子基序之间的接触。利用degron系统，该课题组发现去除中介复合物组分改变了精细尺度的启动子结构，核小体耗散在转录因子驱动的增强子-启动子接触中起着关键作用。该课题组观察到染色质被核小体耗尽区域划分为纳米级结构域。这种结构构象是通过对染色质理化性质的化学特异性粗粒度分子动力学模拟再现的。将MCCu与分子动力学模拟和超分辨率显微镜相结合，使他们能够提出一个统一的模型，其中染色质的生物物理特性协调顺式调控元件之间的接触。
据了解，染色质结构是真核生物基因表达的关键决定因素，但在结合它们的蛋白质的尺度上定义顺式调控元件的结构是不可能的。
附：英文原文
Title: Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions
Author: Hangpeng Li, James L.T. Dalgleish, George Lister, Maria Julia Maristany, Jan Huertas, Ana M. Dopico-Fernandez, Joseph C. Hamley, Nicholas Denny, Gianna Bloye, Weijiao Zhang, Lance Hentges, Roman Doll, Ye Wei, Michela Maresca, Emilia Dimitrova, Lior Pytowski, Edward A.J. Tunnacliffe, Mira Kassouf, Doug Higgs, Elzo de Wit, Robert J. Klose, Lothar Schermelleh, Rosana Collepardo-Guevara, Thomas A. Milne, James O.J. Davies
Issue&Volume: 2025-11-05
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.
DOI: 10.1016/j.cell.2025.10.013
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01178-X