Biology subjects

Peng, Y.

Publications and source records attributed to Peng, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Microbial virulome and resistome in deep-sea cold seeps pose minimal public health risks

Deep-sea cold seeps host high microbial biomass and biodiversity that thrive on hydrocarbon and inorganic compound seepage, exhibiting diverse ecological functions and unique genetic resources. However, potential health risks from pathogenic or antibiotic-resistant microorganisms in these environments remain largely overlooked, especially during resource exploitation and laboratory research. Here, we analyzed 165 metagenomes and 33 metatranscriptomes from 16 global cold seep sites to investigate the diversity and distribution of virulence factors (VFs), antibiotic resistance genes (ARGs), and mobile genetic elements (MGEs). A total of 2,353 VFs are retrieved in 689 MAGs, primarily associated with non-pathogenic functions like adherence. Additionally, cold seeps harbor nearly 100,000 ARGs, as important reservoirs, with high-risk ARGs presenting at low abundance. Compared to other environments, microorganisms in cold seeps exhibit substantial differences in VF and ARG counts, with potential horizontal gene transfer facilitating their spread. These virulome and resistome profiles provide valuable insights into the evolutionary and ecological implications of pathogenicity and antibiotic resistance in extreme deep-sea ecosystems. Collectively, these results indicate that cold seep sediments pose minimal public health risks, shedding lights on environmental safety in deep-sea resource exploitation and research. ImportanceUnderstanding pathogenicity and antibiotic resistance in environmental reservoirs like deep-sea cold seeps is critical for assessing public health risks, particularly with increasing human activities such as deep-sea mining. This study offers the first comprehensive analysis of virulome, resistome, and mobilome profiles in cold seep microbial communities. While cold seeps act as reservoirs for diverse ARGs, high-risk ARGs are rare, and most VFs contribute to non-pathogenic ecological functions. These results highlight the minimal threat to public health posed by cold seeps, providing a reference for monitoring the spread of pathogenicity and resistance in extreme ecosystems and informing environmental safety assessments during deep-sea resource exploitation.

microbiology↗

bioRxiv2024

Diverse quorum sensing systems regulate microbial communication and biogeochemical processes in deep-sea cold seeps

Quorum sensing is a fundamental chemical communication mechanism that enables microorganisms to coordinate behavior and adapt to environmental conditions. In deep-sea cold seep ecosystems, where diverse microbial communities thrive, quorum sensing is likely a key mechanism driving microbial interactions. However, the distribution, mechanisms, and ecological roles of quorum sensing in cold seeps remain poorly understood. To address this, we analyzed 173 metagenomes, 33 metatranscriptomes, and 18 metabolomes from 17 global cold seep sites. We identified 299,355 quorum sensing genes from the seep non-redundant gene catalog, representing 34 gene types across six quorum sensing systems, with distribution patterns influenced by sediment depth and seep type. These quorum sensing genes were present in 3,576 metagenome-assembled genomes from 12 archaeal and 108 bacterial phyla, revealing a complex network of intraspecies and interspecies communication. Microbial groups involved in key metabolic processes, such as sulfate-reducing bacteria, anaerobic methanotrophic archaea, diazotrophs and organohalide reducers, were extensively regulated by quorum sensing, influencing biogeochemical cycles of carbon, nitrogen, and sulfur. Phylogenetic analysis and protein domain identification highlighted the functional roles of key quorum sensing-related proteins (e.g., PDEs, CahR, RpfC/G and LuxR) in modulating microbial behaviors, such as motility and chemotaxis. Heterologous expression and metabolomic profiling further confirmed the activity of representative LuxI-R pairs and identified inhibitors of quorum sensing in cold seep sediments. Overall, these findings highlight complexity and significance of quorum sensing in microbial interactions, ecological adaptation, and biogeochemical cycling within cold seep ecosystems, advancing our understanding of microbial communication in the deep biosphere.

microbiology↗

bioRxiv2024

Systematic identification and characterization of virus lncRNAs suggests extensive structural mimicry of host lncRNAs

Virus long non-coding RNAs (vlncRNAs) play crucial roles in viral infections, yet their identification and characterization remain limited. This study identified 5,053 novel vlncRNAs across 25 viral species using third-generation sequencing, with two from Influenza A virus and Vesicular stomatitis virus validated by RT-qPCR. Most vlncRNAs originated from dsDNA viruses. Only 1% having annotated RNA families, suggesting many novel RNA structures. Although only seven vlncRNAs shared sequence similarities with human lncRNAs (hlncRNAs), 772 vlncRNAs from 15 human viruses structurally mimicked hlncRNAs. These vlncRNA and hlncRNAs bound to similar miRNAs, potentially acting as miRNA sponges to promote essential life process. Splicing analysis showed vlncRNAs had a prevalence of alternative first exon. Finally, we developed vlncRNAbase (http://computationalbiology.cn/vlncRNAbase/#/) to store and organize the newly identified and known vlncRNAs. Overall, the study provides a valuable resource for further investigation into vlncRNAs and deepens our understanding of the diversity, structure and function of the molecule.

bioinformatics↗

bioRxiv2024

Brain-wide population activity during reaching integrates action-mediated goal expectation

Anticipating the outcomes of actions is central to goal-directed behaviour, but how such expectations are encoded across the brain during ongoing movement remains unclear. To address this, we recorded spiking activity from cortical and subcortical regions using multiple Neuropixels probes simultaneously in head-fixed mice performing a water-reaching task. We found that distributed neural population dynamics were strongly modulated by the availability of reward beyond their encoding of forelimb kinematics. Principal component analysis revealed conserved population dynamics across brain regions and sessions that depended on reach amplitude and reward availability. Generalized linear models revealed outcome-related encoding within region-specific population dynamics, in addition to kinematic encoding, with the strongest outcome signals expressed in frontal cortico-thalamic regions. Unsupervised cluster analysis further identified outcome-encoding subpopulations that were enriched in frontal cortices and disproportionally contributed to the shared global latent dynamics. Together, these findings demonstrate that action-mediated outcome expectations are encoded in movement-related population dynamics that are shaped by functional clusters of neurons across the brain.

neuroscience↗

bioRxiv2024

Ligand-Receptor Interactions for Cell-Cell Communication Analysis in Rat, Chicken, Pig, and Monkey Single-Cell and Spatial Transcriptomics

Cell-cell communication is a frequently used analysis approach in single cell RNA and spatial transcriptomics, and many tools like CellPhoneDB, CellChat and stLearn have been developed. Ligand-receptor interactions are the core of cell-cell communication analysis. Since receptor-ligand and even protein-protein interactions were focus on humans and mice research, curated human and mouse receptor-ligand databases have been established, cell-cell interactions for these two species single-cell RNA sequencing data can be directly analyzed. However, for rats, chickens, pigs, monkeys, and other species, cell-cell interaction analysis is often implemented through orthologous gene mapping, due to the lack of curated ligand-receptor interaction databases for these species. We collected cell-cell interaction data mainly from KEGG for rats, chickens, pigs, and monkeys, and extended the data from Reactome and IntAct. Then, by using CellChatV2 with our collected rat ligand-receptor interactions and CellChatV2s own mouse data, respectively, we analyzed 10x Genomics rat public scRNA data, and found that 70 significantly ligand-receptor interactions from the mouse analysis result were also significantly in rats. We also obtained some chicken, pig, and monkey scRNA data from published literature, and analyzed cell-cell interactions using our collected ligand-receptor interactions for these species, and it was proved that our data is reliable and useful. Lastly, we have transformed the ligand-receptor interactions for rat, chicken, pig, and monkey species into the CellChatDB format, which enables swift and straightforward analysis of cell-cell communication in single-cell and spatial data of these four species. All the ligand-receptor interaction datasets for rats, chickens, pigs, and monkeys, as well as the program codes, are available at https://github.com/qingchen36/ligand-receptor. Using our program, one can rapidly obtain receptor-ligand interaction data for other species.

bioinformatics↗

bioRxiv2024

NMI induces chemokine release and recruits neutrophils through the activation of NF-kappaB pathway

Neutrophils are essential components of the innate immune system, playing a pivotal role in immune responses. These cells rapidly migrate to sites of inflammation or tissue injury, facilitating pathogen clearance and tissue repair. The chemotactic signaling network regulating neutrophil recruitment is complex and not fully understood, particularly regarding damage-associated molecular patterns (DAMPs). In our previous research, we identified NMI as a DAMP that activates dendritic cells and macrophages, amplifying inflammatory responses and contributing to both acute and chronic inflammation. In this study, we investigated the role of NMI in neutrophil recruitment. We purified and characterized a recombinant murine NMI protein, ensuring endotoxin removal while preserving biological activity. In vivo experiments demonstrated that NMI enhances neutrophil recruitment in both a murine air pouch model and an acute peritonitis model, mediated by macrophage-derived chemokines. In vitro assays revealed a concentration-dependent increase in neutrophil migration induced by NMI, facilitated by chemokine secretion and subsequent migration through the CXCR2 receptor. Importantly, we established that NMI activates chemokine expression via the NF-{kappa}B signaling pathway. These findings provide insights into the mechanisms of NMI-induced neutrophil migration, enhancing our understanding of neutrophil recruitment during inflammation.

immunology↗

bioRxiv2024

Modeling the antigenic evolution of seasonal influenza viruses with PREDAC for vaccine strain selection in the season of 2025

IntroductionThe antigenic evolution of seasonal influenza viruses have been reported to be discontinuous as clusters. Timely identification of antigenic clusters could help for influenza virus vaccine strain selections. MethodsHere, we revealed the antigenic evolution of seasonal influenza viruses, including A(H3N2), A(H1N1pdm) and B-Victoria, using our previously developed PREDAC methods, and identified antigenic clusters of seasonal influenza viruses based on existing HA protein sequences in GISAID database. ResultsDuring the last six months (2024.2[~]2024.7), for the influenza A(H3N2) virus, the antigenic clusters DA21 (A/Darwin/6/2021-like and A/Massachusetts/18/2022-like) continuously dominated and nearly all viruses are antigenic similar to the current vaccine strain A/Massachusetts/18/2022; for the influenza A(H1N1pdm) virus, the antigenic cluster SY21 (A/Sydney/5/2021-like and A/Victoria/4897/2022-like) dominated and nearly all viruses are antigenic similar to the current vaccine strain A/Victoria/4897/2022; for the influenza B-Victoria, antigenic clusters AU21 (B/Austria/1359417/2021-like) dominated and nearly all viruses are antigenic similar to the current vaccine strain B/Austria/1359417/2021. ConclusionThe analysis suggests that there is no need to update the vaccine strains in the flu season of 2025 on the aspect of antigenicity.

microbiology↗

bioRxiv2024

Dysbiosis-associated gut bacterium Ruminococcus gnavus varies at the strain level in ability to utilize key mucin component sialic acid

Ruminococcus gnavus is a prevalent human gut commensal bacterium with known roles in intestinal mucus degradation, including by catabolism of the terminal mucin sugar sialic acid. While R. gnavus is not considered a pathogen, overabundance of this species is correlated with Inflammatory Bowel Disease (IBD), and its sialic acid metabolism may play a role in the dysbiotic state. Interestingly, liberation of mucin-bound sialic acid by R. gnavus yields the distinct product of 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), in contrast to other known mucin-degrading bacteria, which generate Neu5Ac. This prompted us to look for 2,7-anhydro-Neu5Ac metabolism proteins in the genomes of 77 R. gnavus clinical isolates. We found that 2,7-anhydro-Neu5Ac metabolism is sporadically distributed in this species with respect to phylogeny and strain origin. We measured sialic acid-dependent growth of 12 sequenced isolates, finding that the presence of 2,7-anhydro-Neu5Ac catabolism proteins was predictive of growth on this substrate. Our analysis also uncovered "partial" 2,7-anhydro-Neu5Ac catabolism pathways in two R. gnavus strains, which we determined constitute the canonical Neu5Ac catabolism pathway, previously unreported in this species. These results reveal a notable diversity of sialic acid catabolism across the R. gnavus species, an essential consideration for further investigations into the importance of this metabolism in mucin degradation and in roles of R. gnavus in IBD and other gut dysbioses.

microbiology↗

bioRxiv2024

CRISPR-mediated chromosome deletion facilitates genetic mapping of Vip3Aa resistance gene within complex genomic region in an invasive global pest

Connecting genetic variation to phenotypes and understanding the underlying biological mechanisms has been a fundamental goal of biological genetics. Here, we used the association analysis to identify a Vip3Aa resistance-associated genomic region in a strain of fall armyworm, JC-R, which exhibits >5000-fold resistance to the Bt toxin Vip3Aa. However, through various analytical approaches and fine-scale mapping across different populations, we demonstrated that this genomic region exhibits strong genetic linkage. The chromosome-level genome of JC-R and its parent strain JC-S were assembled, and extensive structural variations in the linkage regions were identified, which could be responsible for maintaining the linkage. To identify the causal variation within this linked region, a chromosome fragment stepwise knockout strategy based on CRISPR/Cas9 was developed. By crossing with the resistant strain and phenotyping segregating offspring on Vip3Aa-containing diet, we identified a chromosomal segment, KO8, containing the resistant gene. Subsequently, we conducted a comprehensive analysis of the variations in the KO8 region using multi-omics approaches, including genomic data, RNA-seq, proteomic, PacBio long read Iso-seq, and phosphoproteomic data. This analysis identified multiple variations in the chitin synthase gene CHS2, including amino acid substitution, alternative splicing, and changes in phosphorylation sites. After knocking out the CHS2, larvae exhibited over 6777-fold resistance to Vip3Aa. These results demonstrate that the chromosome fragment stepwise knockout strategy is a viable approach for studying complex genomic regions, and highlight the value of comprehensive analysis of genetic variations using multi-omics data. The identified candidate gene could potentially advance monitoring and management of pest resistance to Vip3Aa.

genetics↗

bioRxiv2024

Longevity or Well-being? A Dual-Dimension Structure of Neuroticism

The development of personality traits is often viewed as evolutionarily adaptive. Current neuroticism research, however, predominantly highlights its negative health impacts, neglecting its potential evolutionary advantages. We propose that neuroticisms inter-individual variability can be structured into two distinct geometric dimensions. One, named the Emotional Reactivity-Instability/Distress Spectrum (ERIS), correlates strongly with longevity and is associated with chronic diseases and risk-averse lifestyle. This dimension is underpinned by evolutionarily conserved subcortical brain regions and genes. The other, resembling the overall neuroticism score, is primarily linked to mental and stress-related disorders, as well as life satisfaction. It involves higher-order emotional brain regions and is genetically enriched in human-accelerated regions. Collectively, these dimensions represent a dual-strategy personality framework that optimizes survival and well-being, with the former being evolutionarily conservative and the latter potentially a unique human adaptation.

neuroscience↗

bioRxiv2024

Nuclear FAK aggravates CD8+ T cell exhaustion via the SP1-IL-6 axis in colorectal cancer

Nuclear abnormalities such as nuclear deformation are hallmarks of many diseases, including cancer. Accumulating evidence suggests that the dense and mechanically stiff tumor microenvironment promotes nuclear deformation in cancer cells. However, little is known about how nuclear deformation in neoplastic cells regulates immune exhaustion in the tumor microenvironment. Here, we found that lamin A/C-mediated nuclear stiffening in neoplastic cells promotes the nuclear translocation of phosphorylated focal adhesion kinase (pFAK), which is strongly correlated with the heterogeneity and exhaustion of CD8+ T cells within the spatial context of the tumor microenvironment in human colorectal cancer. Mechanistically, we revealed that increased nuclear tension within tumor cells promotes pFAK nuclear translocation, where nuclear pFAK was found to regulate SP1/IL-6-mediated T-cell exhaustion and the transcription of proinflammatory cytokines/chemokines. Pharmacological inhibition or disruption of pFAK nuclear translocation enhanced antitumor immune responses and synergistically potentiated PD-1 and TIM-3 immunotherapy by increasing CD8+ T-cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. These findings highlight the pivotal role of nuclear tension-mediated pFAK translocation into the tumor cell nucleus in regulating CD8+ T-cell exhaustion, suggesting that pFAK is a promising target for advancing cancer immunotherapy.

immunology↗

bioRxiv2024

PLINDER: The protein-ligand interactions dataset and evaluation resource

Protein-ligand interactions (PLI) are foundational to small molecule drug design. With computational methods striving towards experimental accuracy, there is a critical demand for a well-curated and diverse PLI dataset. Existing datasets are often limited in size and diversity, and commonly used evaluation sets suffer from training information leakage, hindering the realistic assessment of method generalization capabilities. To address these shortcomings, we present PLIN-DER, the largest and most annotated dataset to date, comprising 449,383 PLI systems, each with over 500 annotations, similarity metrics at protein, pocket, interaction and ligand levels, and paired unbound (apo) and predicted structures. We propose an approach to generate training and evaluation splits that minimizes task-specific leakage and maximizes test set quality, and compare the resulting performance of DiffDock when retrained with different kinds of splits.

biochemistry↗

bioRxiv2024

Integrated single-cell RNA-seq analysis revealed PTN secreted by fibroblasts acting on itself and macrophages via SDC4 ligand in myocardial hypertrophy

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by massive myocardial hypertrophy, which is the most frequent cause of sudden death and can lead to heart failure (HF) or stroke. The objective of this study was to explore the communication network among various cells in the heart of pathological HCM derived from transverse aortic constriction (TAC) mouse model, and investigate the potential mechanism through data mining, biological informatics analysis, and experimental validation. Methods and ResultsThe integrated analyses including CellChat, Seurat, gene ontology (GO), pseudo-time trajectory analysis, and weighted gene co-expression network analysis (WGCNA) were performed based on the single-cell RNA-seq data (scRNA-seq). In vitro tests were conducted to verify bioinformatic analysis findings through enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT-qPCR), Edu staining, and transwell assay. In vivo tests were also performed to further verify bioinformatic analysis findings by western blot and immunofluorescence assays based on our established TAC mouse model with myocardial hypertrophy. Our results showed that in the heart of TAC mouse, the interaction between cardiac fibroblasts and macrophages was most common, and the increasing pleiotrophin (PTN) secreted by cardiac fibroblasts could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines, such as TNF-, IL-6, Cox-2, Cd83, Egr2, and IL-10 through acting on its ligand recombinant Syndecan 4 (SDC4), which may affect cardiomyocyte normal function and eventually cause HCM. This study first demonstrated that PTN derived from cardiac fibroblasts may act on SDC4 to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM. ConclusionsIn this study, the complex interaction network between cardiac fibroblasts and macrophages of TAC mice based on the scRNA-seq data was investigated, and we found that the increasing PTN secreted by cardiac fibroblasts under cardiac pressure overload could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines through acting on SDC4 ligand, which may affect cardiomyocyte normal function and eventually cause HCM. In addition, our study suggested that PTN derived from cardiac fibroblasts may act on SDC4 ligand to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM.

cell biology↗

bioRxiv2024

Mapping Individual Differences in the Topological Landscape of Naturalistic Brain Dynamics

Psychiatry seeks to unravel brain dysfunction and individual differences in real-world contexts. Naturalistic stimuli, like movie watching, are increasingly recognized for eliciting complex, context-dependent neural activity with high ecological validity. Yet, current methods often rely on standard paradigms that average data across time, limiting the full potential of such stimuli. Here, we present STIM, a Topological Data Analysis-based framework designed to dynamically track how individuals integrate complex contexts in real time. Applied to large-sample fMRI data from movie watching, STIM constructs a robust low-dimensional dynamical landscape that reflects group consensus while probing individual variations at both global (spanning narratives) and local (within specific narratives) levels. At the global level, individual differences emerge along a center-periphery gradient in the dynamical landscape, which significantly predicts fluid intelligence, underscoring the importance of neural adaptability and diversity. At finer scales, local geometric features correlate with context-specific psychological traits beyond cognition. STIM also captures developmental changes in the dynamical landscape and reveals abnormalities in conditions such as autism. These findings demonstrate that STIM leverages the rich information from movie stimuli and fMRI recordings as neural probes to assess individual differences in cognition and mental health.

neuroscience↗

bioRxiv2024

Bacteroides expand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity

Human gut Bacteroides species encode numerous (eight or more) tightly regulated capsular polysaccharides (CPS). Specialized paralogs of the universal transcription elongation factor NusG, called UpxY (Y), and an anti-Y UpxZ (Z) are encoded by the first two genes of each CPS operon. The Y-Z regulators combine with promoter inversions to limit CPS transcription to a single operon in most cells. Y enhances transcript elongation whereas Z inhibits noncognate Ys. How Y distinguishes among cognate CPS operons and how Z inhibits only noncognate Ys are unknown. Using in-vivo nascent-RNA sequencing and promoter-less in vitro transcription (PIVoT), we establish that Y recognizes a paused RNA polymerase via sequences in both the exposed non-template DNA and the upstream duplex DNA. Y association is aided by novel pause-then-escape nascent RNA hairpins. Z binds non-cognate Ys to directly inhibit Y association. This Y-Z hierarchical regulatory program allows Bacteroides to create CPS subpopulations for optimal fitness.

microbiology↗

bioRxiv2024

Oligopeptide (FK)4 facilitates the determination of the absolute stereochemistry of chiral organic compounds via NMR Spectroscopy

Molecular chirality plays a crucial role in the fields of chemistry and biology. Various nuclear magnetic resonance (NMR) methods have been employed for assignment of stereochemical configurations. Alignment media for measurements of anisotropic parameters contribute to configuration elucidations, while chiral auxiliaries assist in enantiomer discrimination and chiral recognition. However, each method comes with limitations, and the assignment of absolute configuration by NMR remains challenging. In this study, we explored a combined approach for absolute configuration elucidation with the multifaceted application of the oligopeptide (FK)4, which possesses dual functionalities as an alignment medium for anisotropic NMR measurements and a chiral differentiating agent. As an alignment medium, (FK)4 facilitates the analysis of stereochemical features through residual dipolar couplings (RDC), aiding in the structural elucidation of stereoisomers. Moreover, (FK)4 exhibits unique chiral differentiating properties, interacting distinctly with enantiomers and resulting in observable bifurcation of chemical shift signals, in 13C, 1H and 19F spectra. Using isoleucine and xylose as model compounds, we demonstrate how the dual functionality of (FK)4 enables the identification of stereoisomeric structures via RDC parameters and the assignment of enantiomeric configurations through measurements of t2 relaxation time coupled with theoretical simulations. These findings highlight the potential of versatile chiral media as (FK)4 for approaching the elucidation of absolute configurations of organic molecules via combined NMR spectroscopy approaches, with implications for structural characterization and enantiomer discrimination in chemical applications.

biochemistry↗

bioRxiv2024

Viral diversiy within marine biofilms and their potential roles in microbially influenced corrosion

In marine environments, a wide variety of microbes exert an important influence on the corrosion of materials. Viruses are widely distributed in biofilms formed on materials and may influence the corrosion process through interactions with key corrosive microbes. However, our understanding of the viral communities within biofilms and their implications for corrosion remains notably limited. To fill this knowledge gap, we utilized 53 publicly metagenomes to investigate the ecological dynamics of viruses within biofilms on 8 different materials and their potential roles in the corrosion of materials. In biofilms, the type of materials may be the primary factor driving differences in the diversity of viral communities. Viruses within biofilms predominantly belong to Caudoviricetes, and phylogenetic analysis of Caudoviricetes and protein-sharing networks with other environments revealed the presence of numerous novel viral clades in biofilms. The presence of virus-host linkages revealed a close association between viruses and corrosive microbes in biofilms. Viruses play a key role in corrosion by modulating host corrosion-related metabolism. It was observed that viruses could enhance host resistance to metals and antibiotics via horizontal gene transfer. Furthermore, viruses can protect themselves from host antiviral systems through anti-defense systems. Overall, this work illustrates the diversity of viruses within biofilms formed on materials and the intricate interactions between viruses and corrosive microbes, revealing the potential roles of viruses in microbially influenced corrosion.

microbiology↗

bioRxiv2024

Electrostatic interactions in nucleosome and higher-order structures are regulated by protonation state of histone ionizable residue

The nucleosome serves as the fundamental unit of chromatin organization, with electrostatic interactions acting as the driving forces in the folding of nucleosomes into chromatin. Perturbations in cellular pH conditions can lead to changes in the protonation states of titratable histone residues, impacting nucleosome surface electrostatic potentials and interactions. However, the effects of proton uptake or release of histone ionizable groups on nucleosome-partner protein interactions and higher-order chromatin structures remain largely unexplored. Here, we conducted comprehensive analyses of histone titratable residue pKa values in various nucleosome contexts, utilizing 96 experimentally determined structures. We revealed that pH-induced changes in histone residue protonation states modulated nucleosome surface electrostatic potentials and significantly influenced nucleosome-partner protein interactions. Furthermore, we observed that proton uptake or release often accompanied nucleosome-partner protein interactions, facilitating their binding processes. Additionally, using a dataset of 1266 recurrent histone cancer mutations, we systematically characterized their impact on nucleosome surface electrostatics, demonstrating their profound effects on electrostatic interactions between nucleosomes and partner proteins. Finally, our findings suggest that alterations in histone protonation or cancer mutations can also regulate nucleosome self-association, thereby modulating the organization and dynamics of higher-order chromatin structure.

biophysics↗