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; Taekjip Ha

doi:10.1038/s41586-025-08971-7

Native nucleosomes intrinsically encode genome organization principles

Nature. 2025 May 7. doi: 10.1038/s41586-025-08971-7. Online ahead of print.

Authors

Sangwoo Park¹, Raquel Merino-Urteaga^#^{2

3}, Violetta Karwacki-Neisius^#^{2

4}, Gustavo Ezequiel Carrizo^#⁵, Advait Athreya^#⁶, Alberto Marin-Gonzalez^{2

4}, Nils A Benning^{2

3}, Jonghan Park⁷, Michelle M Mitchener⁸, Natarajan V Bhanu⁹, Benjamin A Garcia⁹, Bin Zhang¹⁰, Tom W Muir⁸, Erika L Pearce^{5

11}, Taekjip Ha^{12

13

14}

Affiliations

¹ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
³ Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁵ Department of Oncology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Computational and Systems Biology Program, MIT, Cambridge, MA, USA.
⁷ College of Medicine, Yonsei University, Seoul, Republic of Korea.
⁸ Department of Chemistry, Princeton University, Princeton, NJ, USA.
⁹ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine St. Louis, St. Louis, MO, USA.
¹⁰ Department of Chemistry, MIT, Cambridge, MA, USA.
¹¹ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹² Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. taekjip.ha@childrens.harvard.edu.
¹³ Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. taekjip.ha@childrens.harvard.edu.
¹⁴ Department of Pediatrics, Harvard Medical School, Boston, MA, USA. taekjip.ha@childrens.harvard.edu.

^# Contributed equally.

PMID: 40335690
DOI: 10.1038/s41586-025-08971-7

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, respectively^1,2. 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 deficiency^3-5.