Multimodal interactions drive chromatin phase separation and compaction

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(50)

Published: Dec. 4, 2023

Gene silencing is intimately connected to DNA condensation and the formation of transcriptionally inactive heterochromatin by Heterochromatin Protein 1α (HP1α). Because foci are dynamic HP1α can promote liquid-liquid phase separation, HP1α-mediated separation has been proposed as a mechanism chromatin compaction. The molecular basis HP1α-driven compaction associated regulation trimethylation lysine 9 in histone 3 (H3K9me3), which hallmark constitutive heterochromatin, however largely unknown. Using combination assays, site-directed mutagenesis, NMR-based interaction analysis, we show that human compact absence separation. We further demonstrate H3K9-trimethylation promotes arrays through multimodal interactions. results provide insights into thus role gene silencing.

Language: Английский

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Interplay of chromatin organization and mechanics of the cell nucleus

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(19), P. 3386 - 3396

Published: Aug. 8, 2024

Language: Английский

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Role of protein–protein interactions on organization and dynamics of a model chromatin

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 161(13)

Published: Oct. 1, 2024

The three-dimensional organization of chromatin is influenced by chromatin-binding proteins through both specific and non-specific interactions. However, the roles sequence interactions between binding in shaping structure remain elusive. By employing a simple polymer-based model that explicitly considers sequence-dependent protein protein–protein interactions, we elucidate mechanism for organization. We find tuning concentration sufficient to either promote or inhibit compartmentalization. Moreover, attraction strongly affect structural dynamic exponents describe spatiotemporal chromatin. Strikingly, our model’s predictions governing dynamics successfully capture experimental observations, sharp contrast previous models. Overall, findings have potential reinterpret data obtained from various chromosome conformation technologies, laying groundwork advancing understanding

Language: Английский

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Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation

Science Advances, Journal Year: 2024, Volume and Issue: 10(50)

Published: Dec. 11, 2024

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and vitro studies, we show the spatiotemporal formation material properties p53 that might dictate its function. In particular, forms liquid-like nucleus cells, which can bind to DNA perform transcriptional activity. However, cancer-associated mutations promote misfolding partially rigidify with impaired binding ability. Irrespective wild-type mutant forms, partitioning cytoplasm leads condensate formation, subsequently undergoes rapid solidification. studies abundant nuclear components such as RNA nonspecific multicomponent core domain maintain their property, whereas specific promotes dissolution tetrameric functional p53. This work provides mechanistic insights how life cycle be regulated by separation.

Language: Английский

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Reconstructing 3D Biomedical Architectural Order at Multiple Spatial Scales with Multimodal Stack Input

Journal of Bionic Engineering, Journal Year: 2024, Volume and Issue: 21(5), P. 2587 - 2601

Published: June 18, 2024

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: Sept. 27, 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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Nucleo-cytoplasmic environment modulates spatio-temporal p53 phase separation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 18, 2023

Abstract Phase separation of various transcription factors and nucleic acids into biomolecular condensates is known to play an essential role in the regulation gene expression. Here, we show that p53, a tumor suppressor factor, phase separates forms nucleus cancer cells as well when overexpressed cell lines. Although nuclear wild-type (WT) p53 maintain their liquid state are able bind DNA, cancer-associated mutations not only promote misfolding but also partially rigidify condensates, which unable DNA. Irrespective WT or mutant form, cytoplasmic partitioning with time results condensate formation, eventually undergoes rigidification. In vitro , core domain (p53C) process further promoted by mutations. Both RNA non-specific DNA LLPS p53C, specific promotes dissolution p53C condensates. The result suggests cellular microenvironment regulates LLPS, material property its functions.

Language: Английский

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Role of protein-protein interactions on model chromatin organization

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

Published: March 3, 2024

The three-dimensional organization of chromatin is influenced by DNA-binding proteins, through specific and non-specific interactions. However, the role DNA sequence interaction between binding proteins in influencing structure not yet fully understood. By employing a simple polymer-based model chromatin, that explicitly considers sequence-dependent to protein-protein interactions, we elucidate mechanism for organization. We find that: (1) Tuning protein concentration sufficient either promote or inhibit compartmentalization chromatin. (2) presence acts as nucleating site condensation at density lower than isolated systems. (3) exponents describing spatial distance different parts their contact probabilities are strongly both attraction. Our findings have potential application re-interpreting data obtained from various chromosome conformation capture technologies, thereby laying groundwork advancing our understanding

Language: Английский

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Heterogeneity induced Block Copolymer Segregation in Confinement

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

Published: Nov. 3, 2024

Motivated by the work on block copolymer models that provide insights into epigenetics driven chromosome organization, we investigate segregation behavior of five distinct 2-block co-polymers (BCPs) system with varying sizes, confined within both symmetric and lateral geometries. Using exact enumeration method Langevin dynamics simulation, our simple self-avoiding polymer model reveals robust behaviors (across statics dynamic studies) despite strong finite-size effects. We observe as length increases, compaction intensifies relying non-specific interaction, leading to longer times. The study clearly demonstrates formation globular lamellar phases condensed, stable complex structures in long-range (BCP) systems, providing a simplified analogy lamellar-mediated chromatin compaction, which involves are difficult segregate under physiological conditions. Dominance specific interaction over long range BCP systems leads phase separation self assemblies provides heterochromatin—inactive or domains. In contrast, short-range sequences remain coiled state, exhibiting minimal overlap due short attraction, may corresponds euchromatin regions where diverse epigenetic states coexist, resulting active, non-condensed structures. also asymmetric confinement favors more between BCPs irrespective their underlying sequence.

Language: Английский

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Rethinking chromatin accessibility: from compaction to dynamic interactions

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 90, P. 102299 - 102299

Published: Dec. 19, 2024

Language: Английский

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