A Molecular View into the Structure and Dynamics of Phase-Separated Chromatin DOI Creative Commons

Andrew Golembeski,

Joshua Lequieu

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(43), P. 10593 - 10603

Published: Oct. 16, 2024

The organization of chromatin is critical for gene expression, yet the underlying mechanisms responsible this remain unclear. Recent work has suggested that phase separation might play an important role in organization, molecular forces drive are poorly understood. In we interrogate a model to quantify driving and thermodynamics separation. By leveraging multiscale approach, our able reproduce chromatin's chemical structural details at level few nanometers, efficient enough simulate across 100 nm length scales. We first demonstrate can key experiments separating nucleosomal arrays, then apply interactions their formation into condensates with either liquid- or solid-like material properties. next use characterize structure within find irregularly ordered inconsistent existing 30 fiber models. Lastly examine how post-translational modifications modulate acetylation lead decompaction while still preserving Taken together, provides view dynamics phase-separated new insights manifest nucleus living cells.

Language: Английский

From Nucleosomes to Compartments: Physicochemical Interactions Underlying Chromatin Organization DOI
Shuming Liu, Advait Athreya,

Zhuohan Lao

et al.

Annual Review of Biophysics, Journal Year: 2024, Volume and Issue: 53(1), P. 221 - 245

Published: Feb. 12, 2024

Chromatin organization plays a critical role in cellular function by regulating access to genetic information. However, understanding chromatin folding is challenging due its complex, multiscale nature. Significant progress has been made studying vitro systems, uncovering the structure of individual nucleosomes and their arrays, elucidating physicochemical forces stabilizing these structures. Additionally, remarkable advancements have achieved characterizing vivo, particularly at whole-chromosome level, revealing important features such as loops, topologically associating domains, nuclear compartments. bridging gap between vivo studies remains challenging. The resemblance conformations relevance internucleosomal interactions for are subjects debate. This article reviews experimental computational conducted various length scales, highlighting significance intrinsic roles vivo.

Language: Английский

Citations

15
Transferable Implicit Solvation via Contrastive Learning of Graph Neural Networks DOI Creative Commons
Justin Airas, Xinqiang Ding, Bin Zhang

et al.

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(12), P. 2286 - 2297

Published: Nov. 16, 2023

Implicit solvent models are essential for molecular dynamics simulations of biomolecules, striking a balance between computational efficiency and biological realism. Efforts underway to develop accurate transferable implicit coarse-grained (CG) force fields in general, guided by bottom-up approach that matches the CG energy function with potential mean (PMF) defined finer system. However, practical challenges arise due lack analytical expressions PMF algorithmic limitations parameterizing fields. To address these challenges, machine learning-based is proposed, utilizing graph neural networks (GNNs) represent solvation free contrasting parameter optimization. We demonstrate effectiveness deriving GNN model using 600,000 atomistic configurations six proteins obtained from explicit simulations. The provides estimations much more accurately than state-of-the-art models, reproducing configurational distributions also reasonable transferability outside training data. Our study offers valuable insights systematically improvable perspective.

Language: Английский

Citations

14
CG modeling of nucleosome arrays reveals the salt-dependent chromatin fiber conformational variability DOI Creative Commons
Tiedong Sun, Nikolay Korolev, Alexander P. Lyubartsev

et al.

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

Published: Jan. 8, 2025

Eukaryotic DNA is packaged in the cell nucleus into chromatin, composed of arrays DNA–histone protein octamer complexes, nucleosomes. Over past decade, it has become clear that chromatin structure vivo not a hierarchy well-organized folded nucleosome fibers but displays considerable conformational variability and heterogeneity. In vitro studies, as well computational modeling, have revealed attractive nucleosome–nucleosome interaction with an essential role stacking defines compaction. The internal compacted regulated by flexible dynamic histone N-terminal tails. Since highly negatively charged polyelectrolyte, electrostatic forces make decisive contribution to formation require histones, particularly tails, carry significant positive charge. This also results mobile cations cytoplasm (K+, Na+, Mg2+) regulating interactions. Building on previously successfully established bottom-up coarse-grained (CG) model, we developed CG array (chromatin fiber) model explicit presence ions studied its function Na+ Mg2+ ion concentration. With progressively elevated concentrations, identified four main states characterized extended, flexible, nucleosome-clutched, globular fibers.

Language: Английский

Citations

0
Interpretable Protein-DNA Interactions Captured by Structure-Sequence Optimization DOI Open Access

Yafan Zhang,

Irene Silvernail,

Zhuyang Lin

et al.

Published: Feb. 7, 2025

Sequence-specific DNA recognition underlies essential processes in gene regulation, yet methods for simultaneous prediction of genomic sites and their binding affinity remain lacking. Here, we present the Interpretable protein-DNA Energy Associative (IDEA) model, a residue-level, interpretable biophysical model capable predicting affinities DNA-binding proteins. By fusing structures sequences known complexes into an optimized energy IDEA enables direct interpretation physicochemical interactions among individual amino acids nucleotides. We demonstrate that this can accurately predict strengths across various protein families. Additionally, is integrated coarse-grained simulation framework quantitatively captures absolute free energies. Overall, provides computational platform alleviating experimental costs biases assessing be utilized mechanistic studies DNA-recognition processes.

Language: Английский

Citations

0
Interpretable Protein-DNA Interactions Captured by Structure-Sequence Optimization DOI Open Access

Yafan Zhang,

Irene Silvernail,

Zhuyang Lin

et al.

Published: Feb. 7, 2025

Sequence-specific DNA recognition underlies essential processes in gene regulation, yet methods for simultaneous prediction of genomic sites and their binding affinity remain lacking. Here, we present the Interpretable protein-DNA Energy Associative (IDEA) model, a residue-level, interpretable biophysical model capable predicting affinities DNA-binding proteins. By fusing structures sequences known complexes into an optimized energy IDEA enables direct interpretation physicochemical interactions among individual amino acids nucleotides. We demonstrate that this can accurately predict strengths across various protein families. Additionally, is integrated coarse-grained simulation framework quantitatively captures absolute free energies. Overall, provides computational platform alleviating experimental costs biases assessing be utilized mechanistic studies DNA-recognition processes.

Language: Английский

Citations

0
Connected Chromatin Amplifies Acetylation-Modulated Nucleosome Interactions DOI
Ranran Li, Xingcheng Lin

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Histone acetylation is a key regulatory post-translational modification closely associated with gene transcription. In particular, H4K16 (H4K16ac) crucial activation marker that induces an open chromatin configuration. While previous studies have explored the effects of H4K16ac on nucleosome interactions, how this local affects higher-order organization remains unclear. To bridge chemical modifications these histone tail lysine residues to global structure, we utilized residue-resolution coarse-grained model and enhanced sampling techniques simulate charge-neutralization stability, internucleosome structure. Our simulations reveal stabilizes single due reduced entropic contribution tails during DNA unwrapping. addition, modestly weakens interactions by diminishing contacts between tails, DNA, acidic patches. These weakened are amplified when nucleosomes connected linker where increases in entry-exit angles lead significant destacking decompaction, exposing transcriptional activity. findings suggest geometric constraint imposed plays critical role driving structural reorganization upon modifications.

Language: Английский

Citations

0
Chromatin Organization Governs Transcriptional Response and Plasticity of Cancer Stem Cells DOI Creative Commons
Yinu Wang, Jane Frederick, Karla I. Medina

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Chromatin organization regulates transcription to influence cellular plasticity and cell fate. We explored whether chromatin nanoscale packing domains are involved in stemness response chemotherapy. Using an optical spectroscopic nanosensing technology we show that ovarian cancer-derived cancer stem cells (CSCs) display upregulation of compared non-CSCs. Cleavage under targets tagmentation (CUT&Tag) sequencing with antibodies for repressive H3K27me3 active H3K4me3 H3K27ac marks mapped regions associated differentially expressed genes. More poised genes marked by both were identified CSCs vs. non-CSCs, supporting increased transcriptional CSCs. Pathways related Wnt signaling cytokine-cytokine receptor interaction repressed while retinol metabolism antioxidant activated Comparative transcriptomic analyses showed higher intercellular heterogeneity at baseline In cisplatin, low expression levels underwent the highest CSCs, demonstrating stress. Epigenome targeting drugs downregulated promoted differentiation. A disruptor telomeric silencing 1-like (Dot1L) inhibitor blocked plasticity, reversing stemness. These findings support harbor upregulated domains, contributing epigenome modifiers can target.

Language: Английский

Citations

0
Toward Predictive Coarse-Grained Simulations of Biomolecular Condensates DOI
Shuming Liu, Cong Wang, Bin Zhang

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Phase separation is a fundamental process that enables cellular organization by forming biomolecular condensates. These assemblies regulate diverse functions creating distinct environments, influencing reaction kinetics, and facilitating processes such as genome organization, signal transduction, RNA metabolism. Recent studies highlight the complexity of condensate properties, shaped intrinsic molecular features external factors temperature pH. Molecular simulations serve an effective approach to establishing comprehensive framework for analyzing these influences, offering high-resolution insights into stability, dynamics, material properties. This review evaluates recent advancements in simulations, with particular focus on coarse-grained 1-bead-per-amino-acid (1BPA) protein models, emphasizes OpenABC, tool designed simplify streamline simulations. OpenABC supports implementation various force fields, enabling their performance evaluation. Our benchmarking identifies inconsistencies phase behavior predictions across even though models accurately capture single-chain statistics. finding underscores need enhanced field accuracy, achievable through enriched training data sets, many-body potentials, advanced optimization techniques. Such refinements could significantly improve predictive capacity bridging details emergent behaviors.

Language: Английский

Citations

0
Dynamics of nucleosomes and chromatin fibers revealed by single-molecule measurements DOI Creative Commons

Si-Hyeong Nho,

Hajin Kim

BMB Reports, Journal Year: 2025, Volume and Issue: 58(1), P. 24 - 32

Published: Jan. 24, 2025

The nucleosome is the fundamental structural unit of chromosome fibers. DNA wraps around a histone octamer to form while neighboring nucleosomes interact higher-order structures and fit gigabase-long DNAs into small volume nucleus. Nucleosomes interrupt access transcription factors genomic region provide regulatory controls gene expression. Biochemical physical cues stimulate wrapping-unwrapping condensation-decondensation dynamics arrays. Nucleosome chromatin fiber organization are influenced by changes in ionic background within nucleus, post-translational modifications proteins, sequence characteristics, such as histone-binding motifs spacing. biophysical measurements, along with silico simulations, have been extensively used study effects on dynamics. In particular, single-molecule measurements revealed novel mechanistic details This minireview elucidates recent findings from these approaches. [BMB Reports 2024; 58(1): 24-32].

Language: Английский

Citations

0
Regulation of chromatin architecture by protein binding: insights from molecular modeling DOI
Stephanie Portillo‐Ledesma, Tamar Schlick

Biophysical Reviews, Journal Year: 2024, Volume and Issue: 16(3), P. 331 - 343

Published: May 9, 2024

Language: Английский

Citations

2