- Physical Review Journals
All JournalsPhysics Magazine

PRX Life

Reuse & Permissions

It is not necessary to obtain permission to reuse this article or its components as it is available under the terms of the Creative Commons Attribution 4.0 International license. This license permits unrestricted use, distribution, and reproduction in any medium, provided attribution to the author(s) and the published article's title, journal citation, and DOI are maintained. Please note that some figures may have been included with permission from other third parties. It is your responsibility to obtain the proper permission from the rights holder directly for these figures.

Export citation

Export citation

Choose format for download:

Download Citation
  • Open Access

Epigenetic Memory Achieved Through Chromatin-Induced Phase Separation

Adrien Berard1,2, Jacob R. Gissinger3, Kim Sneppen2,*, and Genevieve Thon1,†

  • *Contact author: sneppen@nbi.ku.dk
  • †Contact author: gen@bio.ku.dk
PDF

PRX Life 4, 033016 – Published 18 August, 2026

DOI: https://doi.org/10.1103/pbvj-gj48

Abstract

Chromatin structure is a key determinant of gene expression and epigenetic inheritance. It relies on the post-translational modification of histones, the three-dimensional organization of nucleosomal DNA and interactions between chromatin components. To investigate interplays between these elements, we employed molecular dynamics simulations that integrated polymer modeling with enzymatic reactions on nucleosomes catalyzed by read-write enzymes. We explicitly modeled the diffusible heterochromatic nucleosome reader Swi6 (an HP1 homolog) that engages in homotypic and heterotypic interactions, undergoes and induces conformational changes upon binding to heterochromatic nucleosomes, and facilitates the targeted recruitment of histone deacetylases. The model revealed bistable epigenetic states with a silent state associated to the phase separation of heterochromatic domain condensates. Condensates were supported by Swi6 in a dosage-dependent manner that can be recapitulated in an analytic mean-field approximation. Our model of heterochromatic condensates further showed how a heterochromatic region can induce silencing of another region through spatial proximity in three dimensions. Moreover, extensions of the model suggested a mechanism for how negative feedback from antisilencing factors, here fission yeast Epe1, could confine the spreading of the heterochromatic state by acting on the surface of the condensates, altogether leading to epigenetically stable, spatially restricted chromatin states.

View figure in article

Physics Subject Headings (PhySH)

Collections

This article appears in the following collection:

Collection on Physics of Biomolecular Condensates

From the fundamentals of phase separation, dynamics and structure of condensates in biological settings, to advanced imaging methods, this special collection presented by PRX Life showcases exciting and timely work on the physics of biomolecular condensates.

This Invited Collection is coordinated by PRX Life Associate Editor Christoph Weber, in consultation with Jerelle Joseph, Simon Alberti, and Tanja Mittag. Every article published in this collection underwent a rigorous peer review process, adhering to the same high standards applied to all papers handled by the journal. The PRX Life editorial team managed the peer review and made all editorial decisions.

Article Text

Supplemental Material

References (120)

  1. A. Janssen, S. U. Colmenares, and G. H. Karpen, Heterochromatin: Guardian of the genome, Annu. Rev. Cell Dev. Biol. 34, 265 (2018).
  2. T. Cremer and C. Cremer, Chromosome territories, nuclear architecture and gene regulation in mammalian cells, Nat. Rev. Genet. 2, 292 (2001).
  3. E. Lieberman-Aiden, N. L. van Berkum, L. Williams, M. Imakaev, T. Ragoczy, A. Telling, I. Amit, B. R. Lajoie, P. J. Sabo, M. O. Dorschner, R. Sandstrom, B. Bernstein, M. A. Bender, M. Groudine, A. Gnirke, J. Stamatoyannopoulos, L. A. Mirny, E. S. Lander, and J. Dekker, Comprehensive mapping of long-range interactions reveals folding principles of the human genome, Science 326, 289 (2009).
  4. J. C. R. Politz, D. Scalzo, and M. Groudine, The redundancy of the mammalian heterochromatic compartment, Curr. Opin. Genet. Dev. 37, 1 (2016).
  5. G. Cavalli and T. Misteli, Functional implications of genome topology, Nat. Struct. Mol. Biol. 20, 290 (2013).
  6. A. Soufi, G. Donahue, and K. S. Zaret, Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome, Cell 151, 994 (2012).
  7. W. Zhang, J. Li, K. Suzuki, J. Qu, P. Wang, J. Zhou, X. Liu, R. Ren, X. Xu, A. Ocampo, T. Yuan, J. Yang, Y. Li, L. Shi, D. Guan, H. Pan, S. Duan, Z. Ding, M. Li, F. Yi, et al., A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging, Science 348, 1160 (2015).
  8. T. Chandra, P. A. Ewels, S. Schoenfelder, M. Furlan-Magaril, S. W. Wingett, K. Kirschner, J. Y. Thuret, S. Andrews, P. Fraser, and W. Reik, Global reorganization of the nuclear landscape in senescent cells, Cell Rep. 10, 471 (2015).
  9. J. Padeken, S. P. Methot, and S. M. Gasser, Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance, Nat. Rev. Mol. Cell Biol. 23, 623 (2022).
  10. E. Heitz, Das Heterochromatin der Moose, Jahrb. Wiss. Bot. 69, 762 (1928).
  11. L. Guelen, L. Pagie, E. Brasset, W. Meuleman, M. B. Faza, W. Talhout, B. H. Eussen, A. de Klein, L. Wessels, W. de Laat, and B. van Steensel, Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions, Nature (London) 453, 948 (2008).
  12. Y. Hirano, H. Asakawa, T. Sakuno, T. Haraguchi, and Y. Hiraoka, Nuclear envelope proteins modulating the heterochromatin formation and functions in fission yeast, Cells 9, 1908 (2020).
  13. A. Gonzalez-Sandoval, B. D. Towbin, V. Kalck, D. S. Cabianca, D. Gaidatzis, M. H. Hauer, L. Geng, L. Wang, T. Yang, X. Wang, K. Zhao, and S. M. Gasser, Perinuclear anchoring of H3K9-methylated chromatin stabilizes induced cell fate in C. elegans embryos, Cell 163, 1333 (2015).
  14. M. Falk, Y. Feodorova, N. Naumova, M. Imakaev, B. R. Lajoie, H. Leonhardt, B. Joffe, J. Dekker, G. Fudenberg, I. Solovei, and L. A. Mirny, Heterochromatin drives compartmentalization of inverted and conventional nuclei, Nature (London) 570, 395 (2019).
  15. Q. Bian, E. C. Anderson, Q. Yang, and B. J. Meyer, Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring, Proc. Natl. Acad. Sci. USA 117, 11459 (2020).
  16. T. Montavon, N. Shukeir, G. Erikson, B. Engist, M. Onishi-Seebacher, D. Ryan, Y. Musa, G. Mittler, A. G. Meyer, C. Genoud, and T. Jenuwein, Complete loss of H3K9 methylation dissolves mouse heterochromatin organization, Nat. Commun. 12, 4359 (2021).
  17. F. Zenk, Y. Zhan, P. Kos, E. Löser, N. Atinbayeva, M. Schächtle, G. Tiana, L. Giorgetti, and N. Iovino, HP1 drives de novo 3D genome reorganization in early Drosophila embryos, Nature (London) 593, 289 (2021).
  18. M. J. Johnston, J. J. Y. Lee, B. Hu, A. Nikolic, E. Hasheminasabgorji, A. Baguette, S. Paik, H. Chen, S. Kumar, C. C. L. Chen, S. Jessa, P. Balin, V. Fong, M. Zwaig, K. A. Michealraj, X. Chen, Y. Zhang, S. Varadharajan, P. Billon, N. Juretic, et al., TULIPs decorate the three-dimensional genome of PFA ependymoma, Cell 187, 4926 (2024).
  19. J. F. Williams, I. V. Surovtsev, S. M. Schreiner, Z. Chen, G. Raiymbek, H. Nguyen, Y. Hu, J. S. Biteen, S. G. J. Mochrie, K. Ragunathan, and M. C. King, The condensation of HP1α/Swi6 imparts nuclear stiffness, Cell Rep. 43, 114373 (2024).
  20. D. Thirumalai, G. Shi, S. Shin, and C. Hyeon, Organization and dynamics of chromosomes, Annu. Rev. Phys. Chem. 76, 565 (2025).
  21. M. M. C. Tortora, L. D. Brennan, G. Karpen, and D. Jost, HP1-driven phase separation recapitulates the thermodynamics and kinetics of heterochromatin condensate formation, Proc. Natl. Acad. Sci. USA 120, e2211855120 (2023).
  22. I. B. Dodd, M. A. micheelsen, K. Sneppen, and G. Thon, Theoretical analysis of epigenetic cell memory by nucleosome modification, Cell 129, 813 (2007).
  23. A. Angel, J. Song, C. Dean, and M. Howard, A Polycomb-based switch underlying quantitative epigenetic memory, Nature (London) 476, 105 (2011).
  24. D. Jost, C. Vaillant, and P. Meister, Coupling 1D modifications and 3D nuclear organization: Data, models and function, Curr. Opin. Cell Biol. 44, 20 (2017).
  25. S. H. Sandholtz, Q. MacPherson, and A. J. Spakowitz, Physical modeling of the heritability and maintenance of epigenetic modifications, Proc. Natl. Acad. Sci. USA 117, 20423 (2020).
  26. J. A. Owen, D. Osmanovic, and L. Mirny, Design principles of 3D epigenetic memory systems, Science 382, eadg3053 (2023).
  27. D. Michieletto, E. Orlandini, and D. Marenduzzo, Polymer model with epigenetic recoloring reveals a pathway for the de novo establishment and 3D organization of chromatin domains, Phys. Rev. X 6, 041047 (2016).
  28. D. Michieletto, M. Chiang, D. Colà, A. Papantonis, E. Orlandini, P. R. Cook, and D. Marenduzzo, Shaping epigenetic memory via genomic bookmarking, Nucl. Ac. Res. 46, 83 (2018).
  29. N. Haddad, D. Jost, and C. Vaillant, Perspectives: Using polymer modeling to understand the formation and function of nuclear compartments, Chromos. Res. 25, 35 (2017).
  30. D. Jost and C. Vaillant, Epigenomics in 3D: Importance of long-range spreading and specific interactions in epigenomic maintenance, Nucl. Ac. Res. 46, 2252 (2018).
  31. D. Colì, E. Orlandini, D. Michieletto, and D. Marenduzzo, Magnetic polymer models for epigenetics-driven chromosome folding, Phys. Rev. E 100, 052410 (2019).
  32. K. Adachi and K. Kawaguchi, Chromatin state switching in a polymer model with mark-conformation coupling, Phys. Rev. E 100, 060401(R) (2019).
  33. L. E. J. Skjegstad, J. F. Nickels, K. Sneppen, and J. B. Kirkegaard, Epigenetic switching with asymmetric bridging interactions, Biophys. J. 122, 2421 (2023).
  34. A. Z. Abdulla, Painters in chromatin: Theoretical models for 3D propagation of epigenetic marks, Ph.D. thesis, Ecole normale supérieure de Lyon, 2022.
  35. J. U. Sommer, H. Merlitz, and H. Schiessel, Polymer-assisted condensation: A mechanism for hetero-chromatin formation and epigenetic memory, Macromolecules 55, 4841 (2022).
  36. S. Mukherjee, E. Skoruppa, H. Merlitz, J. U. Sommer, and H. Schiessel, A self-organized liquid reaction container for cellular memory, Adv. Sci. 13, e12500 (2026).
  37. A. Z. Abdulla, C. Vaillant, and D. Jost, Painters in chromatin: A unified quantitative framework to systematically characterize epigenome regulation and memory, Nucl. Ac. Res. 50, 9083 (2022).
  38. G. Thon and T. Friis, Epigenetic inheritance of transcriptional silencing and switching competence in fission yeast, Genetics 145, 685 (1997).
  39. S. I. S. Grewal and A. J. S. Klar, Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis, Cell 86, 95 (1996).
  40. P. N. C. B. Audergon, S. Catania, A. Kagansky, P. Tong, M. Shukla, A. L. Pidoux, and R. C. Allshire, Restricted epigenetic inheritance of H3K9 methylation, Science 348, 132 (2015).
  41. K. Ragunathan, G. Jih, and D. Moazed, Epigenetic inheritance uncoupled from sequence-specific recruitment, Science 348, 1258699 (2015).
  42. S. J. Charlton, V. Flury, Y. Kanoh, A. V. Genzor, L. Kollenstart, W. Ao, P. Brogger, M. B. Weisser, M. Adamus, N. Alcaraz, C. M. Delvaux de Fenffe, F. Mattiroli, G. Montoya, H. Masai, A. Groth, and G. Thon, The fork protection complex promotes parental histone recycling and epigenetic memory, Cell 187, 5029 (2024).
  43. J. Yu, Y. Zhang, Y. Fang, J. A. Paulo, D. Yaghoubi, X. Hua, G. Shipkovenska, T. Toda, Z. Zhang, S. P. Gygi, S. Jia, Q. Li, and D. Moazed, A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance, Cell 187, 5010 (2024).
  44. T. Toda, Y. Fang, C. M. Shan, X. Hua, J. K. Kim, L. C. Tang, M. Jovanovic, L. Tong, F. Qiao, Z. Zhang, and S. Jia, Mrc1 regulates parental histone segregation and heterochromatin inheritance, Mol. Cell 84, 3223 (2024).
  45. S. Rea, F. Eisenhaber, D. O'Carroll, B. D. Strahl, Z. W. Sun, M. Schmid, S. Opravil, K. Mechtler, C. P. Ponting, C. D. Allis, and T. Jenuwein, Regulation of chromatin structure by site-specific histone H3 methyltransferases, Nature (London) 406, 593 (2000).
  46. K. Zhang, K. Mosch, W. Fischle, and S. I. Grewal, Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin, Nat. Struct. Mol. Biol. 15, 381 (2008).
  47. T. Schalch, G. Job, V. J. Noffsinger, S. Shanker, C. Kuscu, L. Joshua-Tor, and J. F. Partridge, High-affinity binding of Chp1 chromodomain to K9 methylated histone H3 is required to establish centromeric heterochromatin, Mol. Cell 34, 36 (2009).
  48. B. Al-Sady, H. D. Madhani, and G. J. Narlikar, Division of labor between the chromodomains of HP1 and Suv39 methylase enables coordination of heterochromatin spread, Mol. Cell 51, 80 (2013).
  49. J. Nakayama, J. C. Rice, B. D. Strahl, C. D. Allis, and S. I. Grewal, Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly, Science 292, 110 (2001).
  50. A. J. Bannister, P. Zegerman, J. F. Partridge, E. A. Miska, J. O. Thomas, R. C. Allshire, and T. Kouzarides, Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain, Nature (London) 410, 120 (2001).
  51. D. Canzio, M. Liao, N. Naber, E. Pate, A. Larson, S. Wu, D. B. Marina, J. F. Garcia, H. D. Madhani, R. Cooke, P. Schuck, Y. Cheng, and G. J. Narlikar, A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly, Nature (London) 496, 377 (2013).
  52. Z. Chen, M. Seman, Y. Fyodorova, A. Farhat, A. Ames, A. Levashkevich, S. Biswas, F. Huang, L. Freddolino, J. S. Biteen, and K. Ragunathan, Tracking live-cell single-molecule dynamics enables measurements of heterochromatin-associated protein–protein interactions, Nucl. Ac. Res. 52, 10731 (2024).
  53. M. R. Motamedi, E. J. Hong, X. Li, S. Gerber, C. Denison, S. Gygi, and D. Moazed, HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms, Mol. Cell 32, 778 (2008).
  54. T. Fischer, B. Cui, J. Dhakshnamoorthy, M. Zhou, C. Rubin, M. Zofall, T. D. Veenstra, and S. I. Grewal, Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast, Proc. Natl. Acad. Sci. USA 106, 8998 (2009).
  55. R. S. Isaac, S. Sanulli, R. Tibble, M. Hornsby, M. Ravalin, C. S. Craik, J. D. Gross, and G. J. Narlikar, Biochemical basis for distinct roles of the heterochromatin proteins Swi6 and Chp2, J. Mol. Biol. 429, 3666 (2017).
  56. G. Raiymbek, S. An, N. Khurana, S. Gopinath, A. Larkin, S. Biswas, R. C. Trievel, U. S. Cho, and K. Ragunathan, An H3K9 methylation-dependent protein interaction regulates the non-enzymatic functions of a putative histone demethylase, eLife 9, e53155 (2020).
  57. T. Yamada, W. Fischle, T. Sugiyama, C. D. Allis, and S. I. Grewal, The nucleation and maintenance of heterochromatin by a histone deacetylase in fission yeast, Mol. Cell 20, 173 (2005).
  58. S. C. Trewick, P. J. McLaughlin, and R. C. Allshire, Methylation: Lost in hydroxylation? EMBO Rep. 6, 315 (2005).
  59. J. Wang, X. Tadeo, H. Hou, P. G. Tu, J. Thompson, J. Yates III, and S. Jia, Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries, Genes Dev. 27, 1886 (2013).
  60. N. P. Cowieson, J. F. Partridge, R. C. Allshire, and P. J. McLaughlin, Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis, Curr. Biol. 10, 517 (2000).
  61. M. Sadaie, R. Kawaguchi, Y. Ohtani, F. Arisaka, K. Tanaka, K. Shirahige, and J. Nakayama, Balance between distinct HP1 family proteins controls heterochromatin assembly in fission yeast, Mol. Cell Biol. 28, 6973 (2008).
  62. D. Canzio, E. Y. Chang, S. Shankar, K. M. Kuchenbecker, M. D. Simon, H. D. Madhani, G. J. Narlikar, and B. Al-Sady, Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging mechanism for heterochromatin assembly, Mol. Cell 41, 67 (2011).
  63. S. Sanulli, M. J. Trnka, V. Dharmarajan, R. W. Tibble, B. D. Pascal, A. L. Burlingame, P. R. Griffin, J. D. Gross, and G. J. Narlikar, HP1 reshapes nucleosome core to promote phase separation of heterochromatin, Nature (London) 575, 390 (2019).
  64. L. Wang, Y. Gao, X. Zheng, C. Liu, S. Dong, R. Li, G. Zhang, Y. Wei, H. Qu, Y. Li, C. D. Allis, G. Li, H. Li, and P. Li, Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism, Mol. Cell 76, 646 (2019).
  65. L. Brennan, H.-K. Kim, S. Colmenares, T. Ego, J.-K. Ryu, and G. Karpen, HP1a promotes chromatin liquidity and drives spontaneous heterochromatin compartmentalization, bioRxiv (2025).
  66. N. Iglesias, J. A. Paulo, A. Tatarakis, X. Wang, A. L. Edwards, N. V. Bhanu, B. A. Garcia, W. Haas, S. P. Gygi, and D. Moazed, Native chromatin proteomics reveals a role for specific nucleoporins in heterochromatin organization and maintenance, Mol. Cell 77, 51 (2020).
  67. H.-S. Kim, B. Roche, S. Bhattacharjee, L. Todeschini, A.-Y. Chang, C. Hammell, A. Verdel, and R. A. Martienssen, Clr4SUV39H1 ubiquitination and non-coding RNA mediate transcriptional silencing of heterochromatin via Swi6 phase separation, Nat. Commun. 15, 9384 (2024).
  68. A. R. Strom, A. V. Emelyanov, M. Mir, D. V. Fyodorov, X. Darzacq, and G. H. Karpen, Phase separation drives heterochromatin domain formation, Nature (London) 547, 241 (2017).
  69. A. G. Larson, D. Elnatan, M. M. Keenen, M. J. Trnka, J. B. Johnston, A. L. Burlingame, D. A. Agard, S. Redding, and G. J. Narlikar, Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin, Nature (London) 547, 236 (2017).
  70. M. M. Keenen, D. Brown, L. D. Brennan, R. Renger, H. Khoo, C. R. Carlson, B. Huang, S. W. Grill, G. J. Narlikar, and S. Redding, HP1 proteins compact DNA into mechanically and positionally stable phase separated domains, eLife 10, e64563 (2021).
  71. S. Bensaha, D. Lewandowska, F. Muzzopappa, S. Hutin, M. D. Tully, M. Anfossi, F. M. Cammas, C. Normand, and F. Erdel, HP1 loses its chromatin clustering and phase separation function across evolution, Nat. Commun. 16, 6375 (2025).
  72. F. Erdel, A. Rademacher, R. Vlijm, J. Tunnermann, L. Frank, R. Weinmann, E. Schweigert, K. Yserentant, J. Hummert, C. Bauer, S. Schumacher, A. Al Alwash, C. Normand, D. P. Herten, J. Engelhardt, and K. Rippe, Mouse heterochromatin adopts digital compaction states without showing hallmarks of HP1-driven liquid-liquid phase separation, Mol. Cell 78, 236 (2020).
  73. N. Akilli, T. Cheutin, and G. Cavalli, Phase separation and inheritance of repressive chromatin domains, Curr. Opin. Genet. Dev. 86, 102201 (2024).
  74. I. M. Hall, G. D. Shankaranarayana, K. Noma, N. Ayoub, A. Cohen, and S. I. Grewal, Establishment and maintenance of a heterochromatin domain, Science 297, 2232 (2002).
  75. M. Zofall, R. Sandhu, S. Holla, D. Wheeler, and S. I. S. Grewal, Histone deacetylation primes self-propagation of heterochromatin domains to promote epigenetic inheritance, Nat. Struct. Mol. Biol. 29, 898 (2022).
  76. J. F. Nickels, M. E. Della-Rosa, I. Miguelez Goyeneche, S. J. Charlton, K. Sneppen, and G. Thon, The transcription factor Atf1 lowers the transition barrier for nucleosome-mediated establishment of heterochromatin, Cell Rep. 39, 110828 (2022).
  77. J. F. Nickels, A. K. Edwards, S. J. Charlton, A. M. Mortensen, S. C. L. Hougaard, A. Trusina, K. Sneppen, and G. Thon, Establishment of heterochromatin in domain-size-dependent bursts, Proc. Natl. Acad. Sci. USA 118, e2022887118 (2021).
  78. M. J. Obersriebnig, E. M. Pallesen, K. Sneppen, A. Trusina, and G. Thon, Nucleation and spreading of a heterochromatic domain in fission yeast, Nat. Commun. 7, 11518 (2016).
  79. A. P. Thompson, H. M. Aktulga, R. Berger, D. S. Bolintineanu, W. M. Brown, P. S. Crozier, P. J. in 't Veld, A. Kohlmeyer, S. G. Moore, T. D. Nguyen, R. Shan, M. J. Stevens, J. Tranchida, C. Trott, and S. J. Plimpton, LAMMPS—A flexible simulation tool for particle-based materials modeling at the atomic, meso, and continuum scales, Comput. Phys. Commun. 271, 108171 (2022).
  80. J. R. Gissinger, B. D. Jensen, and K. E. Wise, Modeling chemical reactions in classical molecular dynamics simulations, Polymer 128, 211 (2017).
  81. J. R. Gissinger, B. D. Jensen, and K. E. Wise, REACTER: A heuristic method for reactive molecular dynamics, Macromolecules 53, 9953 (2020).
  82. J. R. Gissinger, B. D. Jensen, and K. E. Wise, Molecular modeling of reactive systems with REACTER, Comput. Phys. Commun. 304, 109287 (2024).
  83. S. K. Ghosh and D. Jost, How epigenome drives chromatin folding and dynamics, insights from efficient coarse-grained models of chromosomes, PLoS Comput. Biol. 14, e1006159 (2018).
  84. See Supplemental Material at http://link.aps.org/supplemental/10.1103/pbvj-gj48 for Supplemental Figures, Videos, Applets, parameters scans, and additional analysis.
  85. P.-G. De Gennes, Scaling Concepts in Polymer Physics (Cornell University Press, Ithaca, NY, 1979).
  86. M. Rubinstein and R. H. Colby, Polymer Physics (Oxford University Press, Oxford, 2003).
  87. G. Thon, P. Bjerling, C. M. Bunner, and J. Verhein-Hansen, Expression-state boundaries in the mating-type region of fission yeast, Genetics 161, 611 (2002).
  88. K. Noma, H. P. Cam, R. J. Maraia, and S. I. Grewal, A role for TFIIIC transcription factor complex in genome organization, Cell 125, 859 (2006).
  89. J. F. Garcia, B. Al-Sady, and H. D. Madhani, Intrinsic toxicity of unchecked heterochromatin spread is suppressed by redundant chromatin boundary functions in Schizosacchromyces pombe, G3 Genes|Genomes|Genetics 5, 1453 (2015).
  90. E. S. Chen, K. Zhang, E. Nicolas, H. P. Cam, M. Zofall, and S. I. Grewal, Cell cycle control of centromeric repeat transcription and heterochromatin assembly, Nature (London) 451, 734 (2008).
  91. A. Kloc, M. Zaratiegui, E. Nora, and R. Martienssen, RNA interference guides histone modification during the S phase of chromosomal replication, Curr. Biol. 18, 490 (2008).
  92. J. Nakayama, A. J. Klar, and S. I. Grewal, A chromodomain protein, Swi6, performs imprinting functions in fission yeast during mitosis and meiosis, Cell 101, 307 (2000).
  93. T. Mizuguchi, G. Fudenberg, S. Mehta, J. M. Belton, N. Taneja, H. D. Folco, P. FitzGerald, J. Dekker, L. Mirny, J. Barrowman, and S. I. S. Grewal, Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe, Nature (London) 516, 432 (2014).
  94. T. Jakociunas, M. Domange Jordö, M. Aït Mebarek, C. M. Bünner, J. Verhein-Hansen, L. B. Oddershede, and G. Thon, Subnuclear relocalization and silencing of a chromosomal region by an ectopic ribosomal DNA repeat, Proc. Natl. Acad. Sci. USA 110, E4465 (2013).
  95. S. J. Charlton, M. M. Jorgensen, and G. Thon, Integrity of a heterochromatic domain ensured by its boundary elements, Proc. Natl. Acad. Sci. USA 117, 21504 (2020).
  96. N. Ayoub, K. Noma, S. Isaac, T. Kahan, S. I. Grewal, and A. Cohen, A novel jmjC domain protein modulates heterochromatization in fission yeast, Mol. Cell Biol. 23, 4356 (2003).
  97. S. Torres-Garcia, I. Yaseen, M. Shukla, P. Audergon, S. A. White, A. L. Pidoux, and R. C. Allshire, Epigenetic gene silencing by heterochromatin primes fungal resistance, Nature (London) 585, 453 (2020).
  98. I. Yaseen, S. A. White, S. Torres-Garcia, C. Spanos, M. Lafos, E. Gaberdiel, R. Yeboah, M. El Karoui, J. Rappsilber, A. L. Pidoux, and R. C. Allshire, Proteasome-dependent truncation of the negative heterochromatin regulator Epe1 mediates antifungal resistance, Nat. Struct. Mol. Biol. 29, 745 (2022).
  99. M. Zofall, S. Yamanaka, F. E. Reyes-Turcu, K. Zhang, C. Rubin, and S. I. Grewal, RNA elimination machinery targeting meiotic mRNAs promotes facultative heterochromatin formation, Science 335, 96 (2012).
  100. S. Isaac, J. Walfridsson, T. Zohar, D. Lazar, T. Kahan, K. Ekwall, and A. Cohen, Interaction of Epe1 with the heterochromatin assembly pathway in Schizosaccharomyces pombe, Genetics 175, 1549 (2007).
  101. M. Zofall and S. I. Grewal, Swi6/HP1 recruits a JmjC domain protein to facilitate transcription of heterochromatic repeats, Mol. Cell 22, 681 (2006).
  102. S. Braun, J. F. Garcia, M. Rowley, M. Rougemaille, S. Shankar, and H. D. Madhani, The Cul4−Ddb1Cdt2 ubiquitin ligase inhibits invasion of a boundary-associated antisilencing factor into heterochromatin, Cell 144, 41 (2011).
  103. M. A. Micheelsen, N. Mitarai, K. Sneppen, and I. B. Dodd, Theory for the stability and regulation of epigenetic landscapes, Phys. Biol. 7, 026010 (2010).
  104. C. M. Fare, A. Villani, L. E. Drake, and J. Shorter, Higher-order organization of biomolecular condensates, Open Biol. 11, 210137 (2021).
  105. F. M. Kelley, B. Favetta, R. M. Regy, J. Mittal, and B. S. Schuster, Amphiphilic proteins coassemble into multiphasic condensates and act as biomolecular surfactants, Proc. Natl. Acad. Sci. USA 118, e2109967118 (2021).
  106. V. Pandey, T. Hosokawa, Y. Hayashi, and H. Urakubo, Multiphasic protein condensation governed by shape and valency, Cell Rep. 44, 115504 (2025).
  107. L. Zhou, L. Zhu, C. Wang, T. Xu, J. Wang, B. Zhang, X. Zhang, and H. Wang, Multiphasic condensates formed with mono-component of tetrapeptides via phase separation, Nat. Commun. 16, 2706 (2025).
  108. J. Bauermann, G. Bartolucci, J. Boekhoven, C. A. Weber, and F. Jülicher, Formation of liquid shells in active droplet systems, Phys. Rev. Res. 5, 043246 (2023).
  109. A. M. Bergmann, J. Bauermann, G. Bartolucci, C. Donau, M. Stasi, A.-L. Holtmannspötter, F. Jülicher, C. A. Weber, and J. Boekhoven, Liquid spherical shells are a non-equilibrium steady state of active droplets, Nat. Commun. 14, 6552 (2023).
  110. B. A. Gibson, L. K. Doolittle, M. W. G. Schneider, L. E. Jensen, N. Gamarra, L. Henry, D. W. Gerlich, S. Redding, and M. K. Rosen, Organization of chromatin by intrinsic and regulated phase separation, Cell 179, 470 (2019).
  111. M. V. Garabedian, C. Noguchi, M. A. Ziegler, M. M. Das, T. Singh, L. J. Harper, A. R. Leman, L. Khair, B. A. Moser, T. M. Nakamura, and E. Noguchi, The double-bromodomain proteins Bdf1 and Bdf2 modulate chromatin structure to regulate S-phase stress response in Schizosaccharomyces pombe, Genetics 190, 487 (2012).
  112. K. Bao, C. M. Shan, J. Moresco, J. Yates III, and S. Jia, Anti-silencing factor Epe1 associates with SAGA to regulate transcription within heterochromatin, Genes Dev. 33, 116 (2019).
  113. L. Zhou, Z. Chen, Y. Zou, X. Zhang, Z. Wang, H. Zhu, J. Lin, Z. Huang, L. Zheng, J. Chen, M. Xie, M. Zhang, R. Zhang, M. Zhu, Z. Wang, H. Zhou, S. Gao, Y. Yin, Y. Wu, and T. Kang, ASB7 is a negative regulator of H3K9me3 homeostasis, Science 389, 309 (2025).
  114. P. E. Rouse, Jr., A theory of the linear viscoelastic properties of dilute solutions of coiling polymers, J. Chem. Phys. 21, 1272 (1953).
  115. P. M. Morse, Diatomic molecules according to the wave mechanics. II. Vibrational levels, Phys. Rev. 34, 57 (1929).
  116. A. Buckle, C. A. Brackley, S. Boyle, D. Marenduzzo, and N. Gilbert, Polymer simulations of heteromorphic chromatin predict the 3D folding of complex genomic loci, Mol. Cell 72, 786 (2018).
  117. T. Földes, A. Lesage, and M. Barbi, Assessing the polymer coil-globule state from the very first spectral modes, Phys. Rev. Lett. 127, 277801 (2021).
  118. F. García Fernández, S. Huet, and J. Miné-Hattab, Multi-scale imaging of the dynamic organization of chromatin, Int. J. Mol. Sci. 24, 15975 (2023).
  119. https://github.com/Adrien-Berard/epigenetic-memory-phase-separation-Berard2026/tree/main.
  120. A. Berard, J. Gissinger, K. Sneppen, and G. Thon, Epigenetic memory achieved through chromatin-induced phase separation (Version 1.0.2) [Dataset], Zenodo, https://doi.org/10.5281/zenodo.20762561 (2026).

Outline

Information

PRX Life 4, 033016– Published 18 August, 2026
  • Received 8 September 2025
  • Accepted 8 July 2026
Crossmark - Check for updates button
Creative Commons Logo

Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

Published by the American Physical Society

Sign In to Your Journals Account

Filter

Filter

Article Lookup

Enter a citation