The genome in the cell nucleus is organized by a dynamic process influenced by structural memory from mitosis. In this study, we develop a model of human genome dynamics through cell cycles by extending the previously developed whole-genome model to cover the mitotic phase. With this extension, we focus on the role of mitotic and cell cycle memory in genome organization. The simulation progresses from mitosis to interphase and the subsequent mitosis, leading to successive cell cycles. During mitosis, our model describes microtubule dynamics, showing how forces orchestrate the assembly of chromosomes into a rosette ring structure at metaphase. The model explains how the positioning of chromosomes depends on their size in metaphase. The memory of the metaphase configuration persists through mitosis and into interphase in dimensions perpendicular to the cell division axis, effectively guiding the distribution of chromosome territories over multiple cell cycles. At the onset of each G1 phase, phase separation of active and inactive chromatin domains occurs, leading to A/B compartmentalization. Our cycling simulations show that the compartments are unaffected by structural memory from previous cycles and are consistently established in each cell cycle. The genome model developed in this study highlights the interplay between chromosome dynamics and structural memory across cell cycles, providing insights for the analyses of cellular processes.
REFERENCES
1.
J.
Walter
, L.
Schermelleh
, M.
Cremer
, S.
Tashiro
, and T.
Cremer
, “Chromosome order in HeLa cells changes during mitosis and early G1, but is stably maintained during subsequent interphase stages
,” J. Cell Biol.
160
, 685
–697
(2003
).2.
K.
Maeshima
, S.
Ide
, K.
Hibino
, and M.
Sasai
, “Liquid-like behavior of chromatin
,” Curr. Opin. Genet. Dev.
37
, 36
–45
(2016
).3.
S. S.
Ashwin
, T.
Nozaki
, K.
Maeshima
, and M.
Sasai
, “Organization of fast and slow chromatin revealed by single-nucleosome dynamics
,” Proc. Natl. Acad. Sci. U. S. A.
116
, 19939
–19944
(2019
).4.
T.
Nozaki
, S.
Shinkai
, S.
Ide
, K.
Higashi
, S.
Tamura
, M. A.
Shimazoe
, M.
Nakagawa
, Y.
Suzuki
, Y.
Okada
, M.
Sasai
, S.
Onami
, K.
Kurokawa
, S.
Iida
, and K.
Maeshima
, “Condensed but liquid-like domain organization of active chromatin regions in living human cells
,” Sci. Adv.
9
, eadf1488
(2023
).5.
H.
Strickfaden
, T. O.
Tolsma
, A.
Sharma
, D. A.
Underhill
, J. C.
Hansen
, and M. J.
Hendzel
, “Condensed chromatin behaves like a solid on the mesoscale in vitro and in living cells
,” Cell
183
, 1772
–1784.E13
(2020
).6.
A.
Rosa
and R.
Everaers
, “Structure and dynamics of interphase chromosomes
,” PLoS Comput. Biol.
4
, e1000153
(2008
).7.
S.
Fujishiro
and M.
Sasai
, “Generation of dynamic three-dimensional genome structure through phase separation of chromatin
,” Proc. Natl. Acad. Sci. U. S. A.
119
, e2109838119
(2022
).8.
E. M.
Hildebrand
, K.
Polovnikov
, B.
Dekker
, Y.
Liu
, D. L.
Lafontaine
, A. N.
Fox
, Y.
Li
, S. V.
Venev
, L. A.
Mirny
, and J.
Dekker
, “Mitotic chromosomes are self-entangled and disentangle through a topoisomerase-II-dependent two-stage exit from mitosis
,” Mol. Cell
84
, 1422
–1441.E14
(2024
).9.
I.
Solovei
and L.
Mirny
, “Spandrels of the cell nucleus
,” Curr. Opin. Cell Biol.
90
, 102421
(2024
).10.
S. S.
Rao
, M. H.
Huntley
, N. C.
Durand
, E. K.
Stamenova
, I. D.
Bochkov
, J. T.
Robinson
, A. L.
Sanborn
, I.
Machol
, A. D.
Omer
, E. S.
Lander
, and E. L.
Aiden
, “A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping
,” Cell
159
, 1665
–1680
(2014
).11.
T.
Nozaki
, R.
Imai
, M.
Tanbo
, R.
Nagashima
, S.
Tamura
, T.
Tani
, Y.
Joti
, M.
Tomita
, K.
Hibino
, M. T.
Kanemaki
, K. S.
Wendt
, Y.
Okada
, T.
Nagai
, and K.
Maeshima
, “Dynamic organization of chromatin domains revealed by super-resolution live-cell imaging
,” Mol. Cell
67
, 282
–293.E7
(2017
).12.
T.
Misteli
, “The self-organizing genome: Principles of genome architecture and function
,” Cell
183
, 28
–45
(2020
).13.
P. G.
de Gennes
, Scaling Concepts in Polymer Physics
(Cornell University Press
, 1979
).14.
A.
Bolzer
, G.
Kreth
, I.
Solovei
, D.
Koehler
, K.
Saracoglu
, C.
Fauth
, S.
Müller
, R.
Eils
, C.
Cremer
, M. R.
Speicher
, and T.
Cremer
, “Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes
,” PLoS Biol.
3
, e157
(2005
).15.
T.
Cremer
and M.
Cremer
, “Chromosome territories
,” Cold Spring Harbor Perspect. Biol.
2
, a003889
(2010
).16.
T.
Cremer
, M.
Cremer
, and C.
Cremer
, “The 4D nucleome: Genome compartmentalization in an evolutionary context
,” Biochemistry (Moscow)
83
, 313
–325
(2018
).17.
C.
Hoencamp
, O.
Dudchenko
, A. M. O.
Elbatsh
, S.
Brahmachari
, J. A.
Raaijmakers
, T.
van Schaik
, Á.
Sedeño Cacciatore
et al, “3D genomics across the tree of life reveals condensin II as a determinant of architecture type
,” Science
372
, 984
–989
(2021
).18.
S.
Fujishiro
and M.
Sasai
, “Three-dimensional simulation of whole-genome structuring through the transition from anaphase to interphase
,” in Computational Methods for 3D Genome Analysis
, Methods in Molecular Biology
, edited by R.
Nakato
(Springer Nature
, 2024
), pp. 293
–308
.19.
J. H.
Su
, P.
Zheng
, S. S.
Kinrot
, B.
Bintu
, and X.
Zhuang
, “Genome-scale imaging of the 3D organization and transcriptional activity of chromatin
,” Cell
182
, 1641
–1659.E26
(2020
).20.
S.
Boyle
, S.
Gilchrist
, J. M.
Bridger
, N. L.
Mahy
, J. A.
Ellis
, and W. A.
Bickmore
, “The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells
,” Hum. Mol. Genet.
10
, 211
–219
(2001
).21.
M.
Di Stefano
, H. W.
Nützmann
, M. A.
Marti-Renom
, and D.
Jost
, “Polymer modelling unveils the roles of heterochromatin and nucleolar organizing regions in shaping 3D genome organization in Arabidopsis Thaliana
,” Nucleic Acids Res.
49
, 1840
–1858
(2021
).22.
R.
Nagele
, T.
Freeman
, L.
McMorrow
, and H. Y.
Lee
, “Precise spatial positioning of chromosomes during prometaphase: Evidence for chromosomal order
,” Science
270
, 1831
–1835
(1995
).23.
A.
Mogilner
, R.
Wollman
, G.
Civelekoglu-Scholey
, and J.
Scholey
, “Modeling mitosis
,” Trends Cell Biol.
16
, 88
–96
(2006
).24.
J. R.
McIntosh
, M. I.
Molodtsov
, and F. I.
Ataullakhanov
, “Biophysics of mitosis
,” Q. Rev. Biophys.
45
, 147
–207
(2012
).25.
G.
Civelekoglu-Scholey
and D.
Cimini
, “Modelling chromosome dynamics in mitosis: A historical perspective on models of metaphase and anaphase in eukaryotic cells
,” Interface Focus
4
, 20130073
(2014
).26.
S.
Reber
and A. A.
Hyman
, “Emergent properties of the metaphase spindle
,” Cold Spring Harbor Perspect. Biol.
7
, a015784
(2015
).27.
D.
Oriola
, D. J.
Needleman
, and J.
Brugués
, “The physics of the metaphase spindle
,” Annu. Rev. Biophys.
47
, 655
–673
(2018
).28.
V. A.
Valdez
, L.
Neahring
, S.
Petry
, and S.
Dumont
, “Mechanisms underlying spindle assembly and robustness
,” Nat. Rev. Mol. Cell Biol.
24
, 523
–542
(2023
).29.
M. E.
Larson
, B. D.
Harrison
, and K.
Bloom
, “Uncovering chromatin’s contribution to the mitotic spindle: Applications of computational and polymer models
,” Biochimie
92
, 1741
–1748
(2010
).30.
J. S.
Verdaasdonk
and K.
Bloom
, “Centromeres: Unique chromatin structures that drive chromosome segregation
,” Nat. Rev. Mol. Cell Biol.
12
, 320
–332
(2011
).31.
R.
Paul
, R.
Wollman
, W. T.
Silkworth
, I. K.
Nardi
, D.
Cimini
, and A.
Mogilner
, “Computer simulations predict that chromosome movements and rotations accelerate mitotic spindle assembly without compromising accuracy
,” Proc. Natl. Acad. Sci. U. S. A.
106
, 15708
–15713
(2009
).32.
C.
Edelmaier
, A. R.
Lamson
, Z. R.
Gergely
, S.
Ansari
, R.
Blackwell
, J. R.
McIntosh
, M. A.
Glaser
, and M. D.
Betterton
, “Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling
,” Elife
9
, e48787
(2020
).33.
M. A.
Krivov
, F. I.
Ataullakhanov
, and P. S.
Ivanov
, “Computer simulation of merotelic kinetochore-microtubule attachments: Corona size is more important than other cell parameters
,” Chromosome Res.
29
, 327
–349
(2021
).34.
D.
Oriola
, F.
Jülicher
, and J.
Brugués
, “Active forces shape the metaphase spindle through a mechanical instability
,” Proc. Natl. Acad. Sci. U. S. A.
117
, 16154
–16159
(2020
).35.
R. V.
Skibbens
, V. P.
Skeen
, and E. D.
Salmon
, “Directional instability of kinetochore motility during chromosome congression and segregation in mitotic newt lung cells: A push-pull mechanism
,” J. Cell Biol.
122
, 859
–875
(1993
).36.
S. W.
Grill
, K.
Kruse
, and F.
Jülicher
, “Theory of mitotic spindle oscillations
,” Phys. Rev. Lett.
94
, 108104
(2005
).37.
O.
Campàs
and P.
Sens
, “Chromosome oscillations in mitosis
,” Phys. Rev. Lett.
97
, 128102
(2006
).38.
J.
Häfner
, M. I.
Mayr
, M. M.
Möckel
, and T. U.
Mayer
, “Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A
,” Nat. Commun.
5
, 4397
(2014
).39.
F. A.
Habermann
, M.
Cremer
, J.
Walter
, G.
Kreth
, J.
von Hase
, K.
Bauer
, J.
Wienberg
, C.
Cremer
, T.
Cremer
, and I.
Solovei
, “Arrangements of macro- and microchromosomes in chicken cells
,” Chromosome Res.
9
, 569
–584
(2001
).40.
O.
Takenouchi
, Y.
Sakakibara
, and T. S.
Kitajima
, “Live chromosome identifying and tracking reveals size-based spatial pathway of meiotic errors in oocytes
,” Science
385
, eadn5529
(2024
).41.
A. N.
Boettiger
, B.
Bintu
, J. R.
Moffitt
, S.
Wang
, B. J.
Beliveau
, G.
Fudenberg
, M.
Imakaev
, L. A.
Mirny
, C. T.
Wu
, and X.
Zhuang
, “Super-resolution imaging reveals distinct chromatin folding for different epigenetic states
,” Nature
529
, 418
–422
(2016
).42.
Y. T.
Hsiao
, I. H.
Liao
, B. K.
Wu
, H. P. C.
Chu
, and C. L.
Hsieh
, “Probing chromatin condensation dynamics in live cells using interferometric scattering correlation spectroscopy
,” Commun. Biol.
7
, 763
(2024
).43.
M.
Sadaie
, R.
Salama
, T.
Carroll
, K.
Tomimatsu
, T.
Chandra
, A. R.
Young
, M.
Narita
, P. A.
Pérez-Mancera
, D. C.
Bennett
, H.
Chong
, H.
Kimura
, and M.
Narita
, “Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence
,” Genes Dev.
27
, 1800
–1808
(2013
).44.
J.
Kind
, L.
Pagie
, H.
Ortabozkoyun
, S.
Boyle
, S. S.
de Vries
, H.
Janssen
, M.
Amendola
, L. D.
Nolen
, W. A.
Bickmore
, and B.
van Steensel
, “Single-cell dynamics of genome-nuclear lamina interactions
,” Cell
153
, 178
–192
(2013
).45.
S.
Dillinger
, T.
Straub
, and A.
Németh
, “Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation
,” PLoS One
12
, e0178821
(2017
).46.
N.
Naumova
, M.
Imakaev
, G.
Fudenberg
, Y.
Zhan
, B. R.
Lajoie
, L. A.
Mirny
, and J.
Dekker
, “Organization of the mitotic chromosome
,” Science
342
, 948
–953
(2013
).47.
J. H.
Gibcus
, K.
Samejima
, A.
Goloborodko
, I.
Samejima
, N.
Naumova
, J.
Nuebler
, M. T.
Kanemaki
, L.
Xie
, J. R.
Paulson
, W. C.
Earnshaw
, L. A.
Mirny
, and J.
Dekker
, “A pathway for mitotic chromosome formation
,” Science
359
, eaao6135
(2018
).48.
W. F.
Marshall
, J. F.
Marko
, D. A.
Agard
, and J. W.
Sedat
, “Chromosome elasticity and mitotic polar ejection force measured in living drosophila embryos by four-dimensional microscopy-based motion analysis
,” Curr. Biol.
11
, 569
–578
(2001
).49.
C.
Klein
, T.
Cheutin
, M. F.
O’Donohue
, L.
Rothblum
, H.
Kaplan
, A.
Beorchia
, L.
Lucas
, L.
Héliot
, and D.
Ploton
, “The three-dimensional study of chromosomes and upstream binding factor-immunolabeled nucleolar organizer regions demonstrates their nonrandom spatial arrangement during mitosis
,” Mol. Biol. Cell
9
, 3147
–3159
(1998
).50.
L.
Gao
, L.
Shao
, C. D.
Higgins
, J. S.
Poulton
, M.
Peifer
, M. W.
Davidson
, X.
Wu
, B.
Goldstein
, and E.
Betzig
, “Noninvasive imaging beyond the diffraction limit of 3D dynamics in thickly fluorescent specimens
,” Cell
151
, 1370
–1385
(2012
).51.
S.
Cane
, A. A.
Ye
, S. J.
Luks-Morgan
, and T. J.
Maresca
, “Elevated polar ejection forces stabilize kinetochore-microtubule attachments
,” J. Cell Biol.
200
, 203
–218
(2013
).52.
H.
Maiato
, A. M.
Gomes
, F.
Sousa
, and M.
Barisic
, “Mechanisms of chromosome congression during mitosis
,” Biology
6
, 13
(2017
).53.
G. J.
Brouhard
and A. J.
Hunt
, “Microtubule movements on the arms of mitotic chromosomes: Polar ejection forces quantified in vitro
,” Proc. Natl. Acad. Sci. U. S. A.
102
, 13903
–13908
(2005
).54.
J. K.
Monda
and I. M.
Cheeseman
, “The kinetochore–microtubule interface at a glance
,” J. Cell Sci.
131
, jcs214577
(2018
).55.
V.
Varga
, J.
Helenius
, K.
Tanaka
, A. A.
Hyman
, T. U.
Tanaka
, and J.
Howard
, “Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner
,” Nat. Cell Biol.
8
, 957
–962
(2006
).56.
V.
Varga
, C.
Leduc
, V.
Bormuth
, S.
Diez
, and J.
Howard
, “Kinesin-8 motors act cooperatively to mediate length-dependent microtubule depolymerization
,” Cell
138
, 1174
–1183
(2009
).57.
M. I.
Mayr
, S.
Hümmer
, J.
Bormann
, T.
Grüner
, S.
Adio
, G.
Woehlke
, and T. U.
Mayer
, “The human kinesin Kif18A is a motile microtubule depolymerase essential for chromosome congression
,” Curr. Biol.
17
, 488
–498
(2007
).58.
S. L.
Kline-Smith
and C. E.
Walczak
, “Mitotic spindle assembly and chromosome segregation
,” Mol. Cell
15
, 317
–327
(2004
).59.
S.
Soeda
, K.
Yamada-Nomoto
, and M.
Ohsugi
, “The microtubule-binding and coiled-coil domains of Kid are required to turn off the polar ejection force at anaphase
,” J. Cell Sci.
129
, 3609
–3619
(2016
).60.
V.
Krakoviack
, J. P.
Hansen
, and A. A.
Louis
, “Influence of solvent quality on effective pair potentials between polymers in solution
,” Phys. Rev. E
67
, 041801
(2003
).61.
D.
Gerlich
, J.
Beaudouin
, B.
Kalbfuss
, N.
Daigle
, R.
Eils
, and J.
Ellenberg
, “Global chromosome positions are transmitted through mitosis in mammalian cells
,” Cell
112
, 751
–764
(2003
).62.
H.
Strickfaden
, A.
Zunhammer
, S.
van Koningsbruggen
, D.
Köhler
, and T.
Cremer
, “4D chromatin dynamics in cycling cells: Theodor Boveri’s hypotheses revisited
,” Nucleus
1
, 284
–297
(2010
).63.
N.
Ganai
, S.
Sengupta
, and G. I.
Menon
, “Chromosome positioning from activity-based segregation
,” Nucleic Acids Res.
42
, 4145
–4159
(2014
).64.
R.
Nagashima
, K.
Hibino
, S. S.
Ashwin
, M.
Babokhov
, S.
Fujishiro
, R.
Imai
, T.
Nozaki
, S.
Tamura
, T.
Tani
, H.
Kimura
, M.
Shribak
, M. T.
Kanemaki
, M.
Sasai
, and K.
Maeshima
, “Single nucleosome imaging reveals loose genome chromatin networks via active RNA polymerase II
,” J. Cell Biol.
218
, 1511
–1530
(2019
).65.
A.
Zidovska
, D. A.
Weitz
, and T. J.
Mitchison
, “Micron-scale coherence in interphase chromatin dynamics
,” Proc. Natl. Acad. Sci. U. S. A.
110
, 15555
–15560
(2013
).66.
V.
Nunes
, M.
Dantas
, D.
Castro
, E.
Vitiello
, I.
Wang
, N.
Carpi
, M.
Balland
, M.
Piel
, P.
Aguiar
, H.
Maiato
, and J. G.
Ferreira
, “Centrosome-nuclear axis repositioning drives the assembly of a bipolar spindle scaffold to ensure mitotic fidelity
,” Mol. Biol. Cell
31
, 1675
–1690
(2020
).67.
A.
Desai
and T. J.
Mitchison
, “Microtubule polymerization dynamics
,” Annu. Rev. Cell Dev. Biol.
13
, 83
–117
(1997
).68.
L.
Laan
, J.
Husson
, E. L.
Munteanu
, J. W.
Kerssemakers
, and M.
Dogterom
, “Force-generation and dynamic instability of microtubule bundles
,” Proc. Natl. Acad. Sci. U. S. A.
105
, 8920
–8925
(2008
).69.
J. A.
Kaltschmidt
, C. M.
Davidson
, N. H.
Brown
, and A. H.
Brand
, “Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system
,” Nat. Cell Biol.
2
, 7
–12
(2000
).70.
N.
Tang
and W. F.
Marshall
, “Centrosome positioning in vertebrate development
,” J. Cell Sci.
125
, 4951
–4961
(2012
).71.
I.
Solovei
, M.
Kreysing
, C.
Lanctot
, S.
Kosem
, L.
Peichl
, T.
Cremer
, J.
Guck
, and B.
Joffe
, “Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution
,” Cell
137
, 356
–368
(2009
).72.
I.
Solovei
, A. S.
Wang
, K.
Thanisch
, C. S.
Schmidt
, S.
Krebs
, M.
Zwerger
, T. V.
Cohen
, D.
Devys
, R.
Foisner
, L.
Peichl
, H.
Herrmann
, H.
Blum
, D.
Engelkamp
, C. L.
Stewart
, H.
Leonhardt
, and B.
Joffe
, “LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation
,” Cell
152
, 584
–598
(2013
).73.
N.
Abdennur
and L. A.
Mirny
, “Cooler: Scalable storage for Hi-C data and other genomically labeled arrays
,” Bioinformatics
36
, 311
–316
(2020
).© 2025 Author(s). Published under an exclusive license by AIP Publishing.
2025
Author(s)
You do not currently have access to this content.
