波士顿儿童医院Taekjip Ha小组的一项最新研究揭示了原生核小体内在地编码基因组组织原理。该项研究成果发表在2025年5月7日出版的《自然》上。

在这里，该课题组研究了单个核小体是否包含足够的信息，例如，在它们的生物物理特性中，使三维基因组组织进入隔室。该课题组人员纯化天然单核小体到高单分散性和主题多胺的生理浓度，以确定它们的可凝聚性。已知划分为A区室的染色体区域具有低可聚性，而划分为B区室的染色体区域具有高可聚性。染色质聚合物模拟以可冷凝性为唯一输入，不含任何反式因子，重现了A/B区室。可冷凝性也与基因表达强烈反相关，特别是在启动子附近和以细胞类型依赖的方式。因此，单核小体具有与基因开启或关闭相关的生物物理特性。与遗传和表观遗传特征的比较表明，核小体可凝聚性是一种涌现的特性，提供了一个自然轴，在其上投射高维细胞染色质状态。对不同的凝缩剂或组蛋白修饰和突变的分析表明，编码到核小体中的基因组组织原理本质上大多是静电的。由于敲除或抑制鸟氨酸脱羧酶，无主T细胞中的多胺缺失导致超极化可压缩性，这表明当细胞不能依靠多胺将核小体的生物物理特性转化为三维基因组组织时，它们会加强可压缩性对比，这可能解释了多胺缺失所观察到的功能障碍。

据介绍，真核生物基因组被装入147组蛋白核心周围的碱基对组成常染色质和异染色质，分别对应于A区室和B区室。

附：英文原文

Title: Native nucleosomes intrinsically encode genome organization principles

Author: Park, Sangwoo, Merino-Urteaga, Raquel, Karwacki-Neisius, Violetta, Carrizo, Gustavo Ezequiel, Athreya, Advait, Marin-Gonzalez, Alberto, Benning, Nils A., Park, Jonghan, Mitchener, Michelle M., Bhanu, Natarajan V., Garcia, Benjamin A., Zhang, Bin, Muir, Tom W., Pearce, Erika L., Ha, Taekjip

Issue&Volume: 2025-05-07

Abstract: The eukaryotic genome is packed into nucleosomes of 147base pairs around a histone core and is organized into euchromatin and heterochromatin, corresponding to the A and B compartments, respectively1,2. Here we investigated whether individual nucleosomes contain sufficient information for 3D genomic organization into compartments, for example, in their biophysical properties. We purified native mononucleosomes to high monodispersity and used physiological concentrations of polyamines to determine their condensability. The chromosomal regions known to partition into A compartments have low condensability and those for B compartments have high condensability. Chromatin polymer simulations using condensability as the only input, without any trans factors, reproduced the A/B compartments. Condensability is also strongly anticorrelated with gene expression, particularly near the promoters and in a cell type-dependent manner. Therefore, mononucleosomes have biophysical properties associated with genes being on or off. Comparisons with genetic and epigenetic features indicate that nucleosome condensability is an emergent property, providing a natural axis on which to project the high-dimensional cellular chromatin state. Analysis using various condensing agents or histone modifications and mutations indicates that the genome organization principle encoded into nucleosomes is mostly electrostatic in nature. Polyamine depletion in mouse T cells, resulting from either knocking out or inhibiting ornithine decarboxylase, results in hyperpolarized condensability, indicating that when cells cannot rely on polyamines to translate the biophysical properties of nucleosomes to 3D genome organization, they accentuate condensability contrast, which may explain the dysfunction observed with polyamine deficiency3,4,5.

DOI: 10.1038/s41586-025-08971-7

Source: https://www.nature.com/articles/s41586-025-08971-7