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Multiscale structure of chromatin condensates explains phase separation and material properties.

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Title: Multiscale structure of chromatin condensates explains phase separation and material properties.
Authors: Zhou, Huabin (AUTHOR), Huertas, Jan (AUTHOR), Maristany, M. Julia (AUTHOR), Russell, Kieran (AUTHOR), Hwang, June Ho (AUTHOR), Yao, Run-Wen (AUTHOR), Samanta, Nirnay (AUTHOR), Hutchings, Joshua (AUTHOR), Billur, Ramya (AUTHOR), Shiozaki, Momoko (AUTHOR), Zhao, Xiaowei (AUTHOR), Doolittle, Lynda K. (AUTHOR), Gibson, Bryan A. (AUTHOR), Soranno, Andrea (AUTHOR), Riggi, Margot (AUTHOR), Espinosa, Jorge R. (AUTHOR), Yu, Zhiheng (AUTHOR), Villa, Elizabeth (AUTHOR), Collepardo-Guevara, Rosana (AUTHOR), Rosen, Michael K. (AUTHOR)
Source: Science. 12/4/2025, Vol. 390 Issue 6777, p1-14. 14p.
Subjects: Chromatin, Phase separation, Cell anatomy, DNA structure, Thermal stability, Molecular dynamics, Nucleoproteins
Abstract: The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo–electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose nonrandom organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules determines physical properties of chromatin condensates and cellular chromatin organization. Editor's summary: How linear DNA folds into complex, three-dimensional structures within cells has long been a puzzle. Using advanced imaging and simulations, Zhou et al. showed that a small structural change, just five extra DNA bases between nucleosomes, the basic units of DNA packaging, can drastically change how arrays pack together (see the Perspective by Zhang and Ramani). Depending on this spacing, the droplets can behave like liquids or take on solid-like properties. These results demonstrate how subtle structural features shape the physical properties of chromatin, offering insights into genome organization on larger scales. —Di Jiang INTRODUCTION: Biomolecular condensates are membraneless compartments that concentrate macromolecules and contribute to numerous cellular processes. Chromatin, the complex of DNA and histone proteins that stores genetic information, can phase separate into condensates in the test tube and in cells. It has been unclear how individual DNA-histone units (nucleosomes) come together across scales—from single particles to visible condensates—and how these interactions set condensate material properties. In this study, we bridge that gap with a multiscale investigation of chromatin condensates. RATIONALE: Chromatin fibers are composed of nucleosomes connected by DNA linkers. Previous work showed that linker length influences phase separation of fibers, through an unknown structural mechanism. By integrating (i) cryo–electron tomography (cryo-ET) to capture nucleosome organization and fiber structure, (ii) molecular simulations to quantify how histone tails contribute to nucleosome interactions, and (iii) light microscopy to measure droplet dynamics and viscoelasticity, we investigated how the nanoscale arrangement of nucleosomes determines the material properties and stability of chromatin condensates. We sought a multiscale structural framework to connect DNA linker length, nucleosome arrangement, histone tail interactions, and condensate material properties. By integrating insights from each scale, we explained how linker length tunes condensate behavior. Lastly, we compared these in vitro condensates to chromatin domains inside cells. RESULTS: Using synthetic chromatin fibers with 25- or 30–base pair (bp) DNA linkers, we uncovered how differences in linker length lead to different intramolecular geometry and consequent changes in condensate behavior: 1) Nucleosome array structures: (i) 25-bp chromatin forms flexible, open fibers with nucleosomes facing outward; (ii) 30-bp chromatin adopts compact, stacked configurations where nucleosomes interact within fibers, forming two-start helices; (iii) histone tails make different interactions to stabilize the 25- and 30-bp fiber conformations. 2) Nucleosome array interactions in condensates: (i) conformations of 25-bp fibers enable numerous high-affinity intermolecular interactions; (ii) conformations of 30-bp fibers lead to fewer and lower-affinity intermolecular interactions; (iii) histone tails make different interactions to stabilize intermolecular contacts in the two condensate types; (iv) differences in intermolecular interactions explain the greater stability of 25- versus 30-bp condensates. 3) Condensate material properties: (i) the strongly connected 25-bp network yields condensates with viscous and elastic behaviors, with slow molecular diffusion and high resistance to dissolution; (ii) the weakly connected 30-bp network yields condensates with purely viscous behaviors, with more rapid molecular diffusion and ready dissolution by acetylation. 4) Native chromatin parallels: Dense chromatin clusters in human and mouse cells mirror 25-bp condensates, exhibiting nonrandom packing with occasional stacked regions. Cells may use linker length variations to tune chromatin states at short and long length scales. CONCLUSION: By integrating experiments and simulations from single nucleosomes to molecular networks, applied to biochemically reconstituted synthetic chromatin and native chromatin in nuclei, we demonstrate that changes in DNA linker length steer chromatin condensate architecture and mechanics across scales from nanometers to micrometers. This multiscale framework reveals how cells could switch chromatin between material states—affecting gene regulation and genome stability—through changes in nucleosome spacing, histone modifications, or associated factors. Chromatin organization across scales.: Cryo-ET and computer simulations reveal how DNA linker length controls multiscale chromatin organization. Twenty-five–base pair linker chromatin forms open, flexible structures enabling dense intermolecular networks in condensates. Conversely, 30-bp chromatin adopts compact, intramolecular stacked conformations, creating weakly connected networks. These structural difference explain why 25-bp condensates show enhanced phase separation, slower dynamics, and higher viscoelasticity than 30-bp condensates. [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Multiscale structure of chromatin condensates explains phase separation and material properties.
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  Data: <searchLink fieldCode="AR" term="%22Zhou%2C+Huabin%22">Zhou, Huabin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huertas%2C+Jan%22">Huertas, Jan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Maristany%2C+M%2E+Julia%22">Maristany, M. Julia</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Russell%2C+Kieran%22">Russell, Kieran</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hwang%2C+June+Ho%22">Hwang, June Ho</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yao%2C+Run-Wen%22">Yao, Run-Wen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Samanta%2C+Nirnay%22">Samanta, Nirnay</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hutchings%2C+Joshua%22">Hutchings, Joshua</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Billur%2C+Ramya%22">Billur, Ramya</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shiozaki%2C+Momoko%22">Shiozaki, Momoko</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhao%2C+Xiaowei%22">Zhao, Xiaowei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Doolittle%2C+Lynda+K%2E%22">Doolittle, Lynda K.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gibson%2C+Bryan+A%2E%22">Gibson, Bryan A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Soranno%2C+Andrea%22">Soranno, Andrea</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Riggi%2C+Margot%22">Riggi, Margot</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Espinosa%2C+Jorge+R%2E%22">Espinosa, Jorge R.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yu%2C+Zhiheng%22">Yu, Zhiheng</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Villa%2C+Elizabeth%22">Villa, Elizabeth</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Collepardo-Guevara%2C+Rosana%22">Collepardo-Guevara, Rosana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rosen%2C+Michael+K%2E%22">Rosen, Michael K.</searchLink> (AUTHOR)
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– Name: Abstract
  Label: Abstract
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  Data: The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo–electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose nonrandom organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules determines physical properties of chromatin condensates and cellular chromatin organization. Editor's summary: How linear DNA folds into complex, three-dimensional structures within cells has long been a puzzle. Using advanced imaging and simulations, Zhou et al. showed that a small structural change, just five extra DNA bases between nucleosomes, the basic units of DNA packaging, can drastically change how arrays pack together (see the Perspective by Zhang and Ramani). Depending on this spacing, the droplets can behave like liquids or take on solid-like properties. These results demonstrate how subtle structural features shape the physical properties of chromatin, offering insights into genome organization on larger scales. —Di Jiang INTRODUCTION: Biomolecular condensates are membraneless compartments that concentrate macromolecules and contribute to numerous cellular processes. Chromatin, the complex of DNA and histone proteins that stores genetic information, can phase separate into condensates in the test tube and in cells. It has been unclear how individual DNA-histone units (nucleosomes) come together across scales—from single particles to visible condensates—and how these interactions set condensate material properties. In this study, we bridge that gap with a multiscale investigation of chromatin condensates. RATIONALE: Chromatin fibers are composed of nucleosomes connected by DNA linkers. Previous work showed that linker length influences phase separation of fibers, through an unknown structural mechanism. By integrating (i) cryo–electron tomography (cryo-ET) to capture nucleosome organization and fiber structure, (ii) molecular simulations to quantify how histone tails contribute to nucleosome interactions, and (iii) light microscopy to measure droplet dynamics and viscoelasticity, we investigated how the nanoscale arrangement of nucleosomes determines the material properties and stability of chromatin condensates. We sought a multiscale structural framework to connect DNA linker length, nucleosome arrangement, histone tail interactions, and condensate material properties. By integrating insights from each scale, we explained how linker length tunes condensate behavior. Lastly, we compared these in vitro condensates to chromatin domains inside cells. RESULTS: Using synthetic chromatin fibers with 25- or 30–base pair (bp) DNA linkers, we uncovered how differences in linker length lead to different intramolecular geometry and consequent changes in condensate behavior: 1) Nucleosome array structures: (i) 25-bp chromatin forms flexible, open fibers with nucleosomes facing outward; (ii) 30-bp chromatin adopts compact, stacked configurations where nucleosomes interact within fibers, forming two-start helices; (iii) histone tails make different interactions to stabilize the 25- and 30-bp fiber conformations. 2) Nucleosome array interactions in condensates: (i) conformations of 25-bp fibers enable numerous high-affinity intermolecular interactions; (ii) conformations of 30-bp fibers lead to fewer and lower-affinity intermolecular interactions; (iii) histone tails make different interactions to stabilize intermolecular contacts in the two condensate types; (iv) differences in intermolecular interactions explain the greater stability of 25- versus 30-bp condensates. 3) Condensate material properties: (i) the strongly connected 25-bp network yields condensates with viscous and elastic behaviors, with slow molecular diffusion and high resistance to dissolution; (ii) the weakly connected 30-bp network yields condensates with purely viscous behaviors, with more rapid molecular diffusion and ready dissolution by acetylation. 4) Native chromatin parallels: Dense chromatin clusters in human and mouse cells mirror 25-bp condensates, exhibiting nonrandom packing with occasional stacked regions. Cells may use linker length variations to tune chromatin states at short and long length scales. CONCLUSION: By integrating experiments and simulations from single nucleosomes to molecular networks, applied to biochemically reconstituted synthetic chromatin and native chromatin in nuclei, we demonstrate that changes in DNA linker length steer chromatin condensate architecture and mechanics across scales from nanometers to micrometers. This multiscale framework reveals how cells could switch chromatin between material states—affecting gene regulation and genome stability—through changes in nucleosome spacing, histone modifications, or associated factors. Chromatin organization across scales.: Cryo-ET and computer simulations reveal how DNA linker length controls multiscale chromatin organization. Twenty-five–base pair linker chromatin forms open, flexible structures enabling dense intermolecular networks in condensates. Conversely, 30-bp chromatin adopts compact, intramolecular stacked conformations, creating weakly connected networks. These structural difference explain why 25-bp condensates show enhanced phase separation, slower dynamics, and higher viscoelasticity than 30-bp condensates. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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