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Heterochromatin drives compartmentalization of inverted and conventional nuclei
Open accessAbstract
The nucleus of mammalian cells displays a distinct spatial segregation of active euchromatic and inactive heterochromatic regions of the genome 1,2. In conventional nuclei, microscopy shows that euchromatin is localized in the nuclear interior and heterochromatin at the nuclear periphery 1,2. Genome-wide chromosome conformation capture (Hi-C) analyses show this segregation as a plaid pattern of contact enrichment within euchromatin and heterochromatin compartments 3, and depletion between them. Many mechanisms for the formation of compartments have been proposed, such as attraction of heterochromatin to the nuclear lamina 2,4, preferential attraction of similar chromatin to each other 1,4-12, higher levels of chromatin mobility in active chromatin 13-15 and transcription-related clustering of euchromatin 16,17. However, these hypotheses have remained inconclusive, owing to the difficulty of disentangling intra-chromatin and chromatin-lamina interactions in conventional nuclei 18. The marked reorganization of interphase chromosomes in the inverted nuclei of rods in nocturnal mammals 19,20 provides an opportunity to elucidate the mechanisms that underlie spatial compartmentalization. Here we combine Hi-C analysis of inverted rod nuclei with microscopy and polymer simulations. We find that attractions between heterochromatic regions are crucial for establishing both compartmentalization and the concentric shells of pericentromeric heterochromatin, facultative heterochromatin and euchromatin in the inverted nucleus. When interactions between heterochromatin and the lamina are added, the same model recreates the conventional nuclear organization. In addition, our models allow us to rule out mechanisms of compartmentalization that involve strong euchromatin interactions. Together, our experiments and modelling suggest that attractions between heterochromatic regions are essential for the phase separation of the active and inactive genome in inverted and conventional nuclei, whereas interactions of the chromatin with the lamina are necessary to build the conventional architecture from these segregated phases.
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“Despite the disruption of Lamin B1, the A/B compartmentalization of the genome remained relatively unaffected which is in concordance with the observations in retinal rod neurons, where despite the loss of heterochromatin interactions with the nuclear lamina, phase separation drives the formation of A/B compartments135.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [135]
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“It has been suggested that A/B compartments may be facilitated by affinity of heterochromatin regions to each other [460, 461].”
BackgroundMulti-contact 3C reveals that the human genome during interphase is largely not entangled
Tavares-Cadete, F., Norouzi, D., Dekker, B., Liu, Y., & Dekker, J. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0506-5 · Cited by 78
RNA polymerase II clusters form in line with surface condensation on regulatory chromatin
Pancholi, A., Klingberg, T., Zhang, W., Prizak, R., Mamontova, I., Noa, A., Sobucki, M., Kobitski, A. Y., Nienhaus, G. U., Zaburdaev, V., et al. (2021) · Molecular Systems Biology · doi:10.15252/msb.202110272 · Cited by 86
“Complex morphologies of phaseseparated droplets can also occur in multi-component condensates (Feric et al, 2016).”
BackgroundCondensate interfacial forces reposition DNA loci and probe chromatin viscoelasticity
Strom, A. R., Kim, Y., Zhao, H., Chang, Y.-C., Orlovsky, N. D., Košmrlj, A., Storm, C., & Brangwynne, C. P. (2024) · Cell · doi:10.1016/j.cell.2024.07.034 · Cited by 91
“14 Aberrant spatiotemporal regulation of chromatin-interacting condensates is associated with diseased states.”
Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer
Tan, S. Y. X., Zhang, J., & Tee, W. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.931493 · Cited by 86
“Nuclear Substructures and Chromosome Territories On top of genomic macro-domains like TADs and A/B compartments, heterochromatinization engenders the 3D nuclear structure (Falk et al., 2019), which consists of regions associated with the nucleolus and nuclear lamina, including pericentric heterochromatin (Guenatri et…”
BackgroundSungalee, S., Liu, Y., Lambuta, R. A., Katanayeva, N., Donaldson Collier, M., Tavernari, D., Roulland, S., Ciriello, G., & Oricchio, E. (2021) · Nature Genetics · doi:10.1038/s41588-021-00842-x · Cited by 70
Bian, Q., Anderson, E. C., Yang, Q., & Meyer, B. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002068117 · Cited by 71
“In a recent simulation study, the compartment organization observed in mammalian cells was best explained by a model in which interactions among heterochromatic regions are energetically favorable (22).”
BackgroundMesoscale phase separation of chromatin in the nucleus
Bajpai, G., Pavlov, D. A., Lorber, D., Volk, T., & Safran, S. A. (2021) · eLife · doi:10.7554/elife.63976 · Cited by 77
Stender, E. G. P., Ray, S., Norrild, R. K., Larsen, J. A., Petersen, D., Farzadfard, A., Galvagnion, C., Jensen, H. M., & Buell, A. K. (2021) · Nature Communications · doi:10.1038/s41467-021-27433-y · Cited by 77
Polymer folding through active processes recreates features of genome organization
Goychuk, A., Kannan, D., Chakraborty, A. K., & Mehran Kardar, A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2221726120 · Cited by 72
Generation of dynamic three-dimensional genome structure through phase separation of chromatin
Fujishiro, S., & Sasai, M. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2109838119 · Cited by 74
“This anomalous chromatin distribution was remedied in the models by assuming the counteracting attractive interactions between chromatin and the nuclear lamina [27, 22].”
Shah, P. P., Keough, K. C., Gjoni, K., Santini, G. T., Abdill, R. J., Wickramasinghe, N. M., Dundes, C. E., Karnay, A. M., Chen, A. C., Salomon, R. E. A., et al. (2023) · Genome biology · doi:10.1186/s13059-023-02849-5 · Cited by 74
“…in nuclear lamins disrupt chromatin organization and cause disease, and absence of nuclear lamins contributes to chromatin inversion (Briand et al., 2018; Falk et al., 2019; Lee et al., 2019; Shah et al., 2021; Solovei et al., 2013; Vadrot et al., 2015; Worman and Bonne, 2007; Zheng and Xie, 2019).”
BackgroundOrder and disorder: abnormal 3D chromatin organization in human disease
Anania, C., & Lupiáñez, D. G. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz028 · Cited by 74
“For example, studies on cells lacking the expression of lamin A/C and lamin B receptor (LBR), like nocturnal animal rods with inverted nuclei [62], show a dramatic relocation of heterochromatin from the periphery to the nuclear center [63].”
BackgroundSoft materials as biological and artificial membranes
Tang, S., Davoudi, Z., Wang, G., Xu, Z., Rehman, T. U., Promiński, A., Tian, B., Bratlie, K. M., Peng, H., & Wang, Q. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00029b · Cited by 72
Li, J., Zhang, J., Liu, J., Zhou, Y., Cai, C., Xu, L., Dai, X., Feng, S., Guo, C., Rao, J., et al. (2021) · GigaScience · doi:10.1093/gigascience/giaa142 · Cited by 70
Tortora, M. M. C., Brennan, L. D., Karpen, G. H., & Jost, D. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211855120 · Cited by 69
“1 C ) was representative of the formation of large chromocenters, it may be unable to describe the existing multiplicity of smaller, spatially distinct HP1 compartments (44), observed during interphase in conventional mammalian nuclei (35).”
BackgroundThe rich inner life of the cell nucleus: dynamic organization, active flows, and emergent rheology
Zidovska, A. (2020) · Biophysical Reviews · doi:10.1007/s12551-020-00761-x · Cited by 71
“…al. 2017), computational simulations suggested that HP1 association with parts of the chromatin fiber could lead to microphase polymer separation of heterochromatin and euchromatin in the absence of a solvent and thus without any hydrodynamic interactions (MacPherson et al. 2018; Falk et al. 2019).”
BackgroundLamina-Dependent Stretching and Unconventional Chromosome Compartments in Early C. elegans Embryos
Sawh, A. N., Shafer, M. E. R., Su, J.-H., Zhuang, X., Wang, S., & Mango, S. E. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.02.006 · Cited by 65
“B compartments also depend on the interaction of DNA with the nuclear lamina to promote and radially sequester heterochromatin in lamina-associated domains (LADs) (Falk et al., 2019; Luperchio et al., 2014; van Steensel and Belmont, 2017).”
BackgroundBRD2 compartmentalizes the accessible genome
Xie, L., Dong, P., Qi, Y., Hsieh, T.-H. S., English, B. P., Jung, S., Chen, X., Marzio, M. D., Casellas, R. C., Chang, H. Y., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01044-9 · Cited by 65
“pAG-Tn5 was ordered from EpiCypher (15-1017).”
Structural insights into p300 regulation and acetylation-dependent genome organisation
Ibrahim, Z., Wang, T., Destaing, O., Salvi, N., Hoghoughi, N., Chabert, C., Rusu, A., Gao, J., Feletto, L., Reynoird, N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35375-2 · Cited by 64
“5c; row 10, 11, Supplementary Movie 1).”
Establishment and evolution of heterochromatin
Liu, J., Ali, M., & Zhou, Q. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14303 · Cited by 74
Feng, Y., Wang, Y., Wang, X., He, X., Chen, Y., Naseri, A., Pederson, T., Zheng, J., Zhang, S., Xiao, X., et al. (2020) · Genome biology · doi:10.1186/s13059-020-02201-1 · Cited by 62
“Heterochromatin drives compartmentalization in the inverted nuclei of rods in nocturnal mammals [10].”
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Principles and functions of pericentromeric satellite DNA clustering into chromocenters
Brändle, F., Frühbauer, B., & Jagannathan, M. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.02.005 · Cited by 62
Determining chromatin architecture with Micro Capture-C
Hamley, J. C., Li, H., Denny, N., Downes, D. J., & Davies, J. O. J. (2023) · Nature Protocols · doi:10.1038/s41596-023-00817-8 · Cited by 62
“Whereas the ‘ B ’ compartments colocalize with heterochromatin, which preferentially localizes toward the nuclear periphery in lamina-associated domains 12 .”
BackgroundData-Driven Polymer Model for Mechanistic Exploration of Diploid Genome Organization
Qi, Y., Reyes, A., Johnstone, S. E., Aryee, M. J., Bernstein, B., & Zhang, B. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.09.009 · Cited by 57
Lamina-associated domains: Tethers and looseners
Manzo, S. G., Dauban, L., & van Steensel, B. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2022.01.004 · Cited by 61
Nuclear and genome dynamics underlying DNA double-strand break repair
Chiolo, I., Altmeyer, M., Legube, G., & Mekhail, K. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00828-1 · Cited by 67
“This effect is reminiscent of the behaviour of H3K9me3 heterochromatin domains, which, when detached from the nuclear lamina, coalesce into large internal heterochromatic foci that can trigger the formation of ‘inverted’ nuclei in extreme cases 210 .”
Exploring chromosomal structural heterogeneity across multiple cell lines
Cheng, R. R., Contessoto, V. G., Aiden, E. L., Wolynes, P. G., Pierro, M. D., & Onuchic, J. N. (2020) · eLife · doi:10.7554/elife.60312 · Cited by 59
Chromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 59
Mesoscale structure–function relationships in mitochondrial transcriptional condensates
Feric, M., Sarfallah, A., Dar, F., Temiakov, D., Pappu, R. V., & Misteli, T. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207303119 · Cited by 57
Dong, P., Tu, X., Liang, Z., Kang, B., & Zhong, S. (2020) · Journal of Experimental Botany · doi:10.1093/jxb/eraa220 · Cited by 60
Metadata
- Authors
- Falk, M., Feodorova, Y., Naumova, N., Imakaev, M., Lajoie, B. R., Leonhardt, H., Joffe, B., Dekker, J., Fudenberg, G., Solovei, I., & Mirny, L. A.
- Affiliations
- Massachusetts Institute of Technology (US)
- Medical University Plovdiv (BG)
- Howard Hughes Medical Institute (US)
- Ludwig-Maximilians-Universität München (DE)
- Gladstone Institutes (US)
- Corresponding author
- Fudenberg, Geoffrey
- Solovei, Irina
- Mirny, Leonid A.
- ORCID
- Venue
- Nature
- Published
- 2019-06
- Volume
- 570
- Issue
- 7761
- Pages
- 395-399
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7206897
- OpenAlex
- W2948487481
- Cited by
- 646
- References
- 55
- Citations by year
- 2026: 50 · 2025: 84 · 2024: 95 · 2023: 90 · 2022: 90 · 2021: 116 · 2020: 88 · 2019: 33
- FWCI
- 28.63
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-08-02)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RM1HG007743, R01HG003143)
- National Institute of General Medical Sciences (R01GM114190)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107980)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- nuclear compartmentalization, heterochromatin, rod photoreceptors, nuclear lamina, euchromatin, pericentromeric heterochromatin, facultative heterochromatin, phase separation, chromosome conformation, chromatin organization, polymer simulation
- MeSH terms
- Animals, Cell Compartmentation, Cell Nucleus, Heterochromatin, Models, Biological, Time Factors, Euchromatin, Nuclear Lamina, Mice
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