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Modelling phase-separation: A physical mechanism to control genome folding and gene regulation

Author

Listed:
  • Fontana, Andrea
  • Corberi, Federico
  • Salerno, Mario
  • Chiariello, Andrea M.

Abstract

Phase-separation plays a critical role within cell nuclei. Indeed, extensive experimental work has been done showing the importance of phase-separated condensates in the cell nucleus at different scales, ranging from liquid droplets of proteins to the bigger nucleoli, and there is growing evidence that this physical mechanism is crucial to orchestrate organization of genome architecture and to control gene regulation. On the other hand, computational and theoretical studies have been done to quantitatively explore the physics of this mechanism as well as its influence on biological processes relevant for genome activity, as formation of contacts between gene-enhancer and chromatin re-modelling. Methods commonly employed to study those systems include models based on classical statistical mechanics and numerical strategies such as Monte Carlo or molecular dynamics simulations. This short review focuses on recent theoretical and computational advances in this research field.

Suggested Citation

  • Fontana, Andrea & Corberi, Federico & Salerno, Mario & Chiariello, Andrea M., 2026. "Modelling phase-separation: A physical mechanism to control genome folding and gene regulation," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 682(C).
  • Handle: RePEc:eee:phsmap:v:682:y:2026:i:c:s0378437125007976
    DOI: 10.1016/j.physa.2025.131145
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    1. Adam G. Larson & Daniel Elnatan & Madeline M. Keenen & Michael J. Trnka & Jonathan B. Johnston & Alma L. Burlingame & David A. Agard & Sy Redding & Geeta J. Narlikar, 2017. "Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin," Nature, Nature, vol. 547(7662), pages 236-240, July.
    2. Sofia A. Quinodoz & Lifei Jiang & Aya A. Abu-Alfa & Troy J. Comi & Hongbo Zhao & Qiwei Yu & Lennard W. Wiesner & Jordy F. Botello & Anita Donlic & Elizabeth Soehalim & Prashant Bhat & Christiane Zorba, 2025. "Mapping and engineering RNA-driven architecture of the multiphase nucleolus," Nature, Nature, vol. 644(8076), pages 557-566, August.
    3. Mattia Conte & Luca Fiorillo & Simona Bianco & Andrea M. Chiariello & Andrea Esposito & Mario Nicodemi, 2020. "Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Andrea M. Chiariello & Alex Abraham & Simona Bianco & Andrea Esposito & Andrea Fontana & Francesca Vercellone & Mattia Conte & Mario Nicodemi, 2024. "Multiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Xingzhao Wen & Zhifei Luo & Wenxin Zhao & Riccardo Calandrelli & Tri C. Nguyen & Xueyi Wan & John Lalith Charles Richard & Sheng Zhong, 2024. "Single-cell multiplex chromatin and RNA interactions in ageing human brain," Nature, Nature, vol. 628(8008), pages 648-656, April.
    6. Ting Xie & Adi Danieli-Mackay & Mariachiara Buccarelli & Mariano Barbieri & Ioanna Papadionysiou & Q. Giorgio D’Alessandris & Claudia Robens & Nadine Übelmesser & Omkar Suhas Vinchure & Liverana Laure, 2024. "Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Joshua A. Riback & Lian Zhu & Mylene C. Ferrolino & Michele Tolbert & Diana M. Mitrea & David W. Sanders & Ming-Tzo Wei & Richard W. Kriwacki & Clifford P. Brangwynne, 2020. "Composition-dependent thermodynamics of intracellular phase separation," Nature, Nature, vol. 581(7807), pages 209-214, May.
    8. Jeong Hyun Ahn & Eric S. Davis & Timothy A. Daugird & Shuai Zhao & Ivana Yoseli Quiroga & Hidetaka Uryu & Jie Li & Aaron J. Storey & Yi-Hsuan Tsai & Daniel P. Keeley & Samuel G. Mackintosh & Ricky D. , 2021. "Phase separation drives aberrant chromatin looping and cancer development," Nature, Nature, vol. 595(7868), pages 591-595, July.
    9. Amy R. Strom & Alexander V. Emelyanov & Mustafa Mir & Dmitry V. Fyodorov & Xavier Darzacq & Gary H. Karpen, 2017. "Phase separation drives heterochromatin domain formation," Nature, Nature, vol. 547(7662), pages 241-245, July.
    10. Mattia Conte & Ehsan Irani & Andrea M. Chiariello & Alex Abraham & Simona Bianco & Andrea Esposito & Mario Nicodemi, 2022. "Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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