Regulation of chromatin microphase separation by binding of protein complexes

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

Published: July 12, 2023

We show evidence of the association RNA polymerase II (RNAP) with chromatin in a core-shell organization, reminiscent microphase separation where cores comprise dense and shell, RNAP low density. These observations motivate our physical model for regulation organization. Here, we as multiblock copolymer, comprising active inactive regions (blocks) that are both poor solvent tend to be condensed absence binding proteins. However, quality can regulated by protein complexes (e.g., transcription factors). Using theory polymer brushes, find such leads swelling which turn modifies spatial organization regions. In addition, use simulations study spherical micelles, whose shells bound complexes. micelles increases number controls their size. Thus, genetic modifications affecting strength chromatin-binding may modulate experienced regulate genome.

Language: Английский

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Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus

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

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Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization

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

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Biophysical aspect of assembly and regulation of nuclear bodies scaffolded by architectural RNA

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: 437(9), P. 169016 - 169016

Published: Feb. 18, 2025

Language: Английский

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The LINC Complex Inhibits Excessive Chromatin Repression

Cells, Journal Year: 2023, Volume and Issue: 12(6), P. 932 - 932

Published: March 18, 2023

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex transduces nuclear mechanical inputs suggested to control chromatin organization gene expression; however, the underlying mechanism is currently unclear. We show here that LINC needed minimize repression in muscle tissue, where nuclei are exposed significant during contraction. To this end, genomic binding profiles Polycomb, Heterochromatin Protein1 (HP1a) repressors, RNA-Pol II were studied Drosophila larval muscles lacking functional complex. A increase Polycomb parallel reduction RNA-Pol-II a set genes was observed. Consistently, enhanced tri-methylated H3K9 H3K27 repressive modifications reduced activation by acetylation found. Furthermore, larger H3K27me3 clusters, redistribution from periphery towards center, detected live mutant muscles. Computer simulation indicated observed dissociation envelope promotes growth clusters. Thus, we suggest promoting chromatin–nuclear binding, restricts size thereby limiting transcription repressor, directing robust fibers.

Language: Английский

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Phase transitions in chromatin: Mesoscopic and mean-field approaches

The Journal of Chemical Physics, Journal Year: 2025, Volume and Issue: 162(2)

Published: Jan. 9, 2025

By means of a minimal physical model, we investigate the interplay two phase transitions at play in chromatin organization: (1) liquid–liquid separation within fluid solvating chromatin, resulting formation biocondensates; and (2) coil–globule crossover fiber, which drives condensation or extension chain. In our species representing domain is embedded binary fluid. This separates to form droplet rich macromolecule (B). Chromatin particles are trapped harmonic potential reproduce coil globular phases an isolated polymer We role material B on radius gyration this find that varies nonmonotonically with respect volume fraction B. behavior reminiscent phenomenon known as co-non-solvency: chain good solvent (S) may collapse when second (here B) added low quantity expands higher concentration. addition, presence finite-size effects transition results qualitatively different impact polymers various sizes. context genetic regulation, suggest size domains condensate proteins key parameters control whether respond increase chromatin-binding by condensing expanding.

Language: Английский

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Nuclear speckle proteins form intrinsic and MALAT1-dependent microphases

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Nuclear speckles are enriched in serine / arginine rich splicing factors (SRSFs), such as SRSF1. Splicing and proteins TDP-43 concentrate into distinct speckle territories to enable pre-mRNA processing. We have discovered that SRSFs block copolymers the protein-specific interplay of inter-block repulsions attractions drives spontaneous microphase separation. This gives rise size-limited, ordered assemblies, 30 - 45 nm diameter. Depending on protein, each comprises several tens hundreds molecules. The sub-micron scale observed cells shown be clusters microphases. regulatory lncRNA MALAT1 binds preferentially SRSF1 microphases enhance separation alter structures. Microphase enables concentration finite numbers assemblies with nanoscale structures can modulated by . Our findings provide a structural framework for functional organization factors.

Language: Английский

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Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system

Science Advances, Journal Year: 2025, Volume and Issue: 11(2)

Published: Jan. 10, 2025

In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate the human genome an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains by interplay of transcription, nucleosome remodeling, and loop extrusion. We show not topologically associated domains. Instead, exist across structure-function life cycle couples heterochromatin transcription in situ, explaining how enzyme inhibition can produce paradoxical decrease destabilizing domain cores. Applied to development aging, pairing at myogenic genes could be disrupted nuclear swelling. sum, represent foundation explore interactions single-cell level health.

Language: Английский

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Local Volume Concentration, Packing Domains and Scaling Properties of Chromatin

eLife, Journal Year: 2024, Volume and Issue: 13

Published: June 12, 2024

We propose the Self Returning Excluded Volume (SR-EV) model for structure of chromatin based on stochastic rules and physical interactions. The SR-EV return generate conformationally defined domains observed by single-cell imaging techniques. From nucleosome to chromosome scales, captures overall organization as a corrugated system, with dense dilute regions alternating in manner that resembles mixing two disordered bi-continuous phases. This particular organizational topology is consequence multiplicity interactions processes occurring nuclei, mimicked proposed rules. Single configuration properties ensemble averages show robust agreement between theoretical experimental results including volume concentration, contact probability, packing domain identification size characterization, scaling behavior. Model suggest there an inherent regardless cell character resistant external forcing such RAD21 degradation.

Language: Английский

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Nuclear RNA: a transcription-dependent regulator of chromatin structure

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(4), P. 1605 - 1615

Published: July 31, 2024

Although the majority of RNAs are retained in nucleus, their significance is often overlooked. However, it now becoming clear that nuclear RNA forms a dynamic structure through interacting with various proteins can influence three-dimensional chromatin. We review emerging evidence for mesh or gel, highlighting interplay between DNA, and RNA-binding (RBPs), assessing critical role protein governing chromatin architecture. also discuss proposed formation regulation gel transcriptional control. suggest may concentrate machinery either by direct binding inducing RBPs to form microphase condensates, nanometre sized membraneless structures distinct properties surrounding medium an enrichment particular macromolecules.

Language: Английский

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