Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila

Ulianov, Sergey V.; Doronin, Semen A.; Khrameeva, Ekaterina E.; Kos, Pavel; Luzhin, Artem V; Starikov, Sergei; Galitsyna, Aleksandra A.; Nenasheva, Valentina V.; Ilyin, Artem A.; Flyamer, Ilya M.; Mikhaleva, Elena A.; Logacheva, Mariya D.; Gelfand, Mikhail S.; Chertovich, Alexander V.; Гаврилов, А. В.; Razin, Sergey V.; Shevelyov, Yuri Y.

doi:10.1038/s41467-019-09185-y

Cited by 93 publications

(202 citation statements)

References 62 publications

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“…Specifically, variations in lamin A/C levels, induced by either its up-or down regulation, or as observed in laminopathy-associated mutations in lamin A/C, drive heterochromatin detachment from the nuclear lamina 13,14 . This was accompanied by chromatin de-condensation and reduced levels of HP1 and H3K9me3 repressive marks in mammals 15,16 , C. elegans 17 as well as in Drosophila cells 18,19 . Taken together, these findings suggested that LADs are specifically sensitive to the levels of lamin A/C at the nuclear lamina.…”

Section: Introductionmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intact Drosophila larvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin selfattractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior.This architecture may be essential for robust transcriptional regulation in fully differentiated cells.

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Section: Introductionmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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“…Actively transcribed regions are spatially associated with nuclear pores or localized in the nuclear interior . Such spatial organization is considerably supported by the nuclear lamina, suggesting a significant role for the lamina in genome organization . Lamins are direct targets of CDKs , an interaction which results in their disassembly and solubilization during nuclear envelope breakdown at mitosis .…”

Section: Challenges Associated With Copying the Complex Epigenomementioning

confidence: 99%

Cell cycle dynamics in the reprogramming of cellular identity

Eastman

Guo

2019

FEBS Letters

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Reprogramming of cellular identity is fundamentally at odds with replication of the genome: cell fate reprogramming requires complex multidimensional epigenomic changes, whereas genome replication demands fidelity. In this review, we discuss how the pace of the genome's replication and cell cycle influences the way daughter cells take on their identity. We highlight several biochemical processes that are pertinent to cell fate control, whose propagation into the daughter cells should be governed by more complex mechanisms than simple templated replication. With this mindset, we summarize multiple scenarios where rapid cell cycle could interfere with cell fate copying and promote cell fate reprogramming. Prominent examples of cell fate regulation by specific cell cycle phases are also discussed. Overall, there is much to be learned regarding the relationship between cell fate reprogramming and cell cycle control. Harnessing cell cycle dynamics could greatly facilitate the derivation of desired cell types.

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“…Similar formulation of domain growth terms as volume constraints in free energy has been used by Nonomura in applications of phase-field methods to multi-cellular growth models (41) and recently also by Lee et al (43) for mathematical modeling of chromocenter patterns of rods. Recent experiments and simulations have been shown that nuclear chromatin organization is highly correlated with integrity of chromatin-lamina scaffold (48,50), which regulates chromatin dynamics during development. To highlight the effect of nuclear shape dynamics on chromatin re-organization it is important to couple the nuclear shape dynamics with chromatin state variables.…”

Section: Introductionmentioning

confidence: 99%

“…These are the two-fluid fluctuating hydrodynamic model of chromatin (40), deterministic phase-field models of multi-cellular domain growth (41, 42) and its mathematical application to rod chromocenter patterning (43), mesoscale polymeric models of chromatin fiber (20-22) and active cellular mechanics models (44-47). We have applied MELON framework to model liquid-liquid phase separation driven reorganization of Drosophila melanogaster nucleus under different conditions which are characteristic for different cell phases (48,49): interphase, active remodeling phases, long-term senescence and nuclear inversion ( Fig 1A). Finally, we note that the generic nature of the MELON framework ( Fig 1B) along with the minimal physical assumptions that we have built into the model of Drosophila nucleus allows drawing broad inferences which should also hold for other eukaryotic nuclei.…”

mentioning

confidence: 99%

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

Laghmach

Pierro

Potoyan

2019

Preprint

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The nuclear envelope segregates the genome of Eukaryota from the cytoplasm. Within the nucleus, chromatin is further compartmentalized into architectures that change throughout the lifetime of the cell. Epigenetic patterns along the chromatin polymer strongly correlate with chromatin compartmentalization and, accordingly, also change during the cell life cycle and at differentiation. Recently, it has been suggested that sub-nuclear chromatin compartmentalization might result from a process of liquid-liquid phase separation orchestrated by the epigenetic marking and operated by proteins that bind to chromatin. Here, we translate these observations into a diffuse interface model of chromatin, which we named MEsoscale Liquid mOdel of Nucleus (MELON). Using this streamlined continuum model of the genome, we study the large-scale rearrangements of chromatin that happen at different stages of the growth and senescence of the cell, and during nuclear inversion events. Particularly, we investigate the role of droplet diffusion, fluctuations, and heterochromatin-lamina interactions during nuclear remodeling. Our results indicate that the physical process of liquid-liquid phase separation, together with surface effects is sufficient to recapitulate much of the large-scale morphology and dynamics of chromatin along the life cycle of cells. SIGNIFICANCE STATEMENTEukaryotic chromatin occupies a few micrometers of nuclear space while remaining dynamic and accessible for gene regulation. The physical state of nuclear chromatin is shaped by the juxtaposition of complex, out of equilibrium processes on one hand and intrinsic polymeric aspect of the genome on the other. Recent experiments have revealed a remarkable ability of disordered nuclear proteins to drive liquid-liquid phase separation of chromatin domains. We have built a mesoscale liquid model of nuclear chromatin which allows dissecting the contribution of liquid behavior of chromatin to nuclear order of eukaryotes. Our results show that liquid-liquid phase separation, together with surface effects is sufficient for recapitulating large-scale morphology and dynamics of chromatin at many stages of the nuclear cycle. Laghmach et alClear evidence of hierarchical compartmentalization in chromatin at multiple scales has emerged through studies employing DNA-DNA proximity ligation assays. First, two genomic compartments were observed (3), named A and B, which were then refined through higher resolution experiments to reveal the existence of even smaller sub-compartments (10). The A and B compartments appear to be enriched in epigenetic markings correlating with transcriptional activation and silencing respectively. Several studies have suggested that chromatin compartmentalization may result from a process of liquid-liquid phase separation orchestrated by the epigenetic markings which collectively act to remodel chromosomal loci (15)(16)(17)(18)(19). The epigenetically driven phase segregation events have shown to emerge right at the nucleosome resolution mediated by protein b...

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Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila

Cited by 93 publications

References 62 publications

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Cell cycle dynamics in the reprogramming of cellular identity

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

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