Native nucleosomes intrinsically encode genome organization principles

Sangwoo Park, Raquel Merino-Urteaga, Violetta Karwacki-Neisius, Gustavo Ezequiel Carrizo, Advait Athreya, Alberto Marin-Gonzalez, Nils A. Benning, Jonghan Park, Michelle M. Mitchener, Natarajan V. Bhanu, Benjamin A. Garcia, Bin Zhang, Tom W. Muir, Erika L. Pearce and Taekjip Ha ()
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Sangwoo Park: Johns Hopkins University School of Medicine
Raquel Merino-Urteaga: Boston Children’s Hospital
Violetta Karwacki-Neisius: Boston Children’s Hospital
Gustavo Ezequiel Carrizo: Johns Hopkins University School of Medicine
Advait Athreya: MIT
Alberto Marin-Gonzalez: Boston Children’s Hospital
Nils A. Benning: Boston Children’s Hospital
Jonghan Park: Yonsei University
Michelle M. Mitchener: Princeton University
Natarajan V. Bhanu: Washington University School of Medicine St. Louis
Benjamin A. Garcia: Washington University School of Medicine St. Louis
Bin Zhang: MIT
Tom W. Muir: Princeton University
Erika L. Pearce: Johns Hopkins University School of Medicine
Taekjip Ha: Johns Hopkins University School of Medicine

Nature, 2025, vol. 643, issue 8071, 572-581

Abstract: Abstract The eukaryotic genome is packed into nucleosomes of 147 base 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 deficiency3–5.

Date: 2025
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DOI: 10.1038/s41586-025-08971-7

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