Genome - nuclear lamina interactions are multivalent and cooperative DOI Creative Commons
Lise Dauban, M Eder,

Marcel de Haas

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 10, 2024

Abstract Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions NL encoded in DNA. Here, we designed an efficient LAD “scrambling” approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series large deletions and inversions span LADs flanking sequences. Mapping these rearrangements revealed a single contacts through multiple act cooperatively or redundantly; some have more affinity for than others can pull neighbouring sequences NL. Genes drawn towards showed often, but always, reduced expression increased H3K9me3 levels. Furthermore, when placed close enough each other. These results elucidate principles govern positioning inside cell nucleus. Highlights Efficient generation by transposon elements. multivalent, subregions being potent tethers others. cooperate promote association Changes often accompanied changes gene activity H3K9me3.

Language: Английский

Depletion of lamins B1 and B2 promotes chromatin mobility and induces differential gene expression by a mesoscale-motion-dependent mechanism DOI Creative Commons
Emily M. Pujadas-Liwag,

Xiaolong Wei,

Nicolas Acosta

et al.

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: March 22, 2024

B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous using Auxin-inducible degron technology.

Language: Английский

Citations

14
Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus DOI Creative Commons
Ali Goktug Attar, Jarosław Paturej, Edward J. Banigan

et al.

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 16, 2024

Abnormal cell nuclear shapes are hallmarks of diseases, including progeria, muscular dystrophy, and many cancers. Experiments have shown that disruption heterochromatin increases in euchromatin lead to deformations, such as blebs ruptures. However, the physical mechanisms through which chromatin governs shape poorly understood. To investigate how might govern morphology, we studied microphase separation a composite coarse-grained polymer elastic shell simulation model. By varying density, composition, heterochromatin-lamina interactions, show phase organization may perturb shape. Increasing density stabilizes lamina against large fluctuations. increasing levels or interactions enhances fluctuations by "wetting"-like interaction. In contrast, insensitive heterochromatin's internal structure. Our simulations suggest peripheral accumulation could while stabilization likely occurs other than organization.

Language: Английский

Citations

9
Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization DOI Creative Commons
Aayush Kant, Zixian Guo,

Vinayak Vinayak

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 21, 2024

Abstract In interphase nuclei, chromatin forms dense domains of characteristic sizes, but the influence transcription and histone modifications on domain size is not understood. We present a theoretical model exploring this relationship, considering chromatin-chromatin interactions, modifications, extrusion. predict that heterochromatic governed by balance among diffusive flux methylated histones sustaining them acetylation reactions in process loop extrusion via supercoiling RNAPII at their periphery, which contributes to reduction. Super-resolution nano-imaging five distinct cell lines confirm predictions indicating absence leads larger heterochromatin domains. Furthermore, accurately reproduces findings regarding how transcription-mediated loss can mitigate impacts excessive cohesin loading. Our shed light role genome organization, offering insights into dynamics potential therapeutic targets.

Language: Английский

Citations

9
Temporally Correlated Active Forces Drive Segregation and Enhanced Dynamics in Chromosome Polymers DOI Creative Commons
Sumitabha Brahmachari, Tomer Markovich, F. C. MacKintosh

et al.

PRX Life, Journal Year: 2024, Volume and Issue: 2(3)

Published: July 23, 2024

Understanding the mechanisms governing structure and dynamics of flexible polymers like chromosomes, especially signatures motor-driven active processes, is great interest in genome biology. We study chromosomes as a coarse-grained polymer model where microscopic motor activity captured via an additive temporally persistent noise. The steady state characterized by two parameters: force, controlling persistent-noise amplitude, correlation time, decay time find that drives correlated motion over long distances regime dynamic compaction into globally collapsed entangled globule. Diminished topological constraints destabilize globule, segments trapped globule move toward periphery, resulting enriched monomer density near periphery. also show heterogeneous leads to segregation highly species from less one, suggesting role chromosome compartmental segregation. Adding experimental-data-derived structures, we loci may mechanically perturb switch compartments established epigenetics-driven passive self-association. key distinguishing are enhanced apparent diffusivity, exploration all regimes (subdiffusion, effective diffusion, superdiffusion) at various lag times, broadened distribution observables exponents. Published American Physical Society 2024

Language: Английский

Citations

9
Droplet Physics and Intracellular Phase Separation DOI Creative Commons
Frank Jülicher, Christoph A. Weber

Annual Review of Condensed Matter Physics, Journal Year: 2023, Volume and Issue: 15(1), P. 237 - 261

Published: Dec. 7, 2023

Living cells are spatially organized by compartments that can nucleate, grow, and dissolve. Compartmentalization emerge phase separation, leading to the formation of droplets in cell's nucleo- or cytoplasm, also called biomolecular condensates. Such organize biochemistry cell providing specific chemical environments space time. These provide transient environments, suggesting relevance nonequilibrium physics as a key unraveling underlying physicochemical principles biological functions living cells. In this review, we highlight coarse-grained approaches capture chemically active emulsions model for condensates orchestrating processes. We discuss dynamics single molecules material properties their cell. Finally, propose wetting, prewetting, surface transitions possibility intracellular surfaces control condensates, membranes, exert mechanical forces.

Language: Английский

Citations

18
Post-Translational Modification of Lamins: Mechanisms and Functions DOI Creative Commons
Mingyue Zheng, Guoxiang Jin, Zhongjun Zhou

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: May 17, 2022

Lamins are the ancient type V intermediate filament proteins contributing to diverse biological functions, such as maintenance of nuclear morphology, stabilization chromatin architecture, regulation cell cycle progression, spatial-temporal gene expressions, and transduction mechano-signaling. Deregulation lamins is associated with abnormal morphology disorganization, leading a variety diseases laminopathy premature aging, might also play role in cancer. Accumulating evidence indicates that functionally regulated by post-translational modifications (PTMs) including farnesylation, phosphorylation, acetylation, SUMOylation, methylation, ubiquitination, O-GlcNAcylation affect protein association or proteins. The mechanisms which these PTMs modified relevant functionality become increasingly appreciated understanding changes provides new insights into molecular underlying laminopathies concerned novel strategies for management. In this review, we discussed range lamin their roles both physiological pathological processes, well potential therapeutic targeting PTMs.

Language: Английский

Citations

28
Chromatin Liquid–Liquid Phase Separation (LLPS) Is Regulated by Ionic Conditions and Fiber Length DOI Creative Commons
Qinming Chen, Lei Zhao,

Aghil Soman

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3145 - 3145

Published: Oct. 6, 2022

The dynamic regulation of the physical states chromatin in cell nucleus is crucial for maintaining cellular homeostasis. Chromatin can exist solid- or liquid-like forms depending on surrounding ions, binding proteins, post-translational modifications and many other factors. Several recent studies suggested that undergoes liquid-liquid phase separation (LLPS) vitro also vivo; yet, controversial conclusions about nature LLPS were observed from studies. These inconsistencies are partially due to deviations buffer conditions induce condensation/aggregation as well differences (nucleosome array) constructs used In this work, we present a detailed characterization effects K+, Mg2+ nucleosome fiber length state property reconstituted arrays. was generally shorter arrays (15-197-601, 15 repeats Widom 601 DNA with 197 bp repeat length) at physiological ion concentrations. contrast, gel- solid-like condensates detected considerably longer 62-202-601 lambda (~48.5 kbp) under same conditions. addition, demonstrated presence reduced BSA acetate not essential process. Overall, study provides comprehensive understanding several factors regarding sheds light mechanism biological relevance vivo.

Language: Английский

Citations

26
Polymer-Assisted Condensation: A Mechanism for Hetero-Chromatin Formation and Epigenetic Memory DOI
Jens‐Uwe Sommer, Holger Merlitz, Helmut Schiessel

et al.

Macromolecules, Journal Year: 2022, Volume and Issue: 55(11), P. 4841 - 4851

Published: May 25, 2022

We consider the formation of droplets from a 2-component liquid mixture induced by large polymer chain that has preferential attraction to one components. assume is in fully miscible state, but far above critical interaction limit two species. show coil acts as chemical potential trap, which can shift inside volume into partially state and thus triggers polymer-bound droplet preferred solvent phase, we denote polymer-assisted condensation (PAC). propose mean-field model predict essential features PAC including phase diagram, perform molecular dynamics simulations predicted behavior robust against fluctuation effects. The properties make it an ideal candidate understand biomolecular condensates cell nucleus, such those formed protein heterochromatin 1 (HP1). organize spatial structure chromatin hetero- euchromatin their stability with respect chromatin-HP1-interaction ensures propagation epigenetic information through generations.

Language: Английский

Citations

23
Explicit ion modeling predicts physicochemical interactions for chromatin organization DOI Creative Commons
Xingcheng Lin, Bin Zhang

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Aug. 21, 2023

Molecular mechanisms that dictate chromatin organization in vivo are under active investigation, and the extent to which intrinsic interactions contribute this process remains debatable. A central quantity for evaluating their contribution is strength of nucleosome-nucleosome binding, previous experiments have estimated range from 2 14 k B T . We introduce an explicit ion model dramatically enhance accuracy residue-level coarse-grained modeling approaches across a wide ionic concentrations. This allows de novo predictions computationally efficient, enabling large-scale conformational sampling free energy calculations. It reproduces energetics protein-DNA binding unwinding single nucleosomal DNA, resolves differential impact mono- divalent ions on conformations. Moreover, we showed can reconcile various quantifying interactions, providing explanation large discrepancy between existing estimations. predict interaction at physiological conditions be 9 , value nonetheless sensitive DNA linker length presence histones. Our study strongly supports physicochemical phase behavior aggregates inside nucleus.

Language: Английский

Citations

16
SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology DOI Creative Commons
Jinzhou Huang, Chenming Wu, Jake A. Kloeber

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(7), P. 1043 - 1060.e10

Published: Feb. 27, 2023

Language: Английский

Citations

13