Pigment Cell Melanoma Res. 2025 May;38(3):e70022. doi: 10.1111/pcmr.70022.

ABSTRACT

Pigment cells not only are intrinsic factors to determine animal patterns, but also play vital roles in numerous behavioral and physiological processes as well as health, such as melanomas originating from melanocytes. Model organisms are commonly used to study pigment cell development and the mechanisms underlying related diseases, with zebrafish and mice, and Xenopus being well-established examples. Xenopus tropicalis, a diploid amphibian model, offers advantages such as high fecundity and easily observable pigment cell development. Recent advancements in gene-editing techniques have increased its prominence in research on pigment cell biology and melanoma pathogenesis. Here, we compare the skin pigment cell distribution as well as the skin structure in X. tropicalis, zebrafish, mice, and humans and point out the potential value of using X. tropicalis to model human skin diseases, such as melanoma.

PMID:40329555 | DOI:10.1111/pcmr.70022

Microbiome. 2025 May 6;13(1):115. doi: 10.1186/s40168-025-02107-9.

ABSTRACT

BACKGROUND: The human microbiome is transmissible between individuals, including pathogens and commensals with metabolic and immune-modulating effects, which could influence susceptibility, severity, and outcomes of both infection and non-infection diseases. However, limited studies of respiratory microbiome transmission within populations have been conducted. Herein, we performed species- and strain-level metagenomic analyses on oropharyngeal (OP) swabs from 1046 healthy urban dwellers across 13 districts, including 111 households with at least two cohabitants, to elucidate the transmission dynamics of the respiratory microbiome within households and communities.

RESULTS: We found that geographic districts accounted for the greatest variation in the OP microbiome, with unrelated individuals from the same district showing greater microbiome similarity and higher strain-sharing rates than those from different districts. Cohabitants, especially spouses and siblings, exhibited similar microbial abundances and shared more strains, with 16.7% (IQR 0.0-33.3%) of strains shared among cohabitants, compared to 0.0% (IQR 0.0-11.1%) in non-cohabiting pairs (p < 0.05). Both respiratory commensals and opportunistic pathogens were shared among cohabitants. In contrast, no evidence of vertical transmission was detected between mother-offspring pairs. Additionally, the OP microbiome contained diverse antibiotic resistance genes (ARGs), with 15.0% linked to mobile genetic elements (MGEs) or plasmids; the flanking sequences of these ARGs were more conserved across species than those of non-MGE-associated ARGs, suggesting horizontal transfer of ARGs among respiratory microorganisms.

CONCLUSIONS: In summary, we characterized the transmissible nature of the OP microbiome and the risk of ARG dissemination among respiratory microorganisms. These findings underscore the role of respiratory microbes and ARGs exchange in shaping the microbiome of healthy populations and emphasize their relevance to public health strategies for respiratory health management. Video Abstract.

PMID:40329426 | DOI:10.1186/s40168-025-02107-9

Mol Syst Biol. 2025 May 6. doi: 10.1038/s44320-025-00107-3. Online ahead of print.

ABSTRACT

Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, and with Polycomb occupancy. We show that histone genes are expressed with allelic imbalance in mESCs, and are involved in haplotype-specific chromatin contacts marked by H3K27me3. Conditional knockouts of Polycomb enzymatic subunits, Ezh2 or Ring1, show that one-third of ASE genes, including histone genes, is regulated through Polycomb repression. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.

PMID:40329044 | DOI:10.1038/s44320-025-00107-3

Sci Rep. 2025 May 6;15(1):15748. doi: 10.1038/s41598-025-99252-w.

ABSTRACT

In May 2022, Mpox outbreaks emerged in regions where the virus is not traditionally prevalent. This study estimates the mean incubation period, serial interval and the extent of presymptomatic transmission in the Arab Gulf Countries (AGC). The effective reproduction number ([Formula: see text]) is also calculated, as well as the degree of heterogeneity ([Formula: see text]), using the instant-individual heterogeneity transmission model. We analyze data from 41 confirmed cases for which we have complete information, estimating the mean incubation period using gamma, Weibull and lognormal distributions, with respective means of 8.52 (95% CI 7.26-9.98), 8.57 (95% CI 7.28-10.01), and 8.64 (95% CI 7.23-10.26) days. The mean serial interval, based on 31 case pairs, was 7.19 days (95% CI 4.11-12.95), 7.16 days (95% CI 5.80-8.90), and 10.0 days (95% CI 6.30-16.3) for the gamma, Weibull, and lognormal distributions, respectively. The Akaike Information Criterion (AIC) validated the best-fitting models. The serial intervals were shorter than the incubation periods, suggesting that pre-symptomatic transmission occurred in 60% of transmission events. We estimated [Formula: see text] to be 0.95 (95% highest posterior density [HPD]: 0.93-1.35) and [Formula: see text] to be 1.52 (95% HPD: 1.07-5.76), indicating supercritical Mpox transmission in the AGC with limited transmission heterogeneity. Using a Bayesian framework with non-informative priors and a negative binomial distribution, we projected [Formula: see text] to remain between 0.95 and 1.0 from August 2022 to January 2023, underscoring the need for continued efforts to reduce transmissibility. These findings provide valuable information for public health interventions, emphasizing a multifaceted approach to managing Mpox transmission.

PMID:40328893 | DOI:10.1038/s41598-025-99252-w

Nat Commun. 2025 May 6;16(1):4216. doi: 10.1038/s41467-025-59416-8.

ABSTRACT

Recycling human urine offers a sustainable solution to environmental challenges posed by conventional wastewater treatment. While it is possible to recover nutrients like nitrogen and phosphorus from urine, the low economic value of these products limits large-scale adoption. Here, we show that engineered yeast can convert urine into hydroxyapatite (HAp), a high-value biomaterial widely used in bone and dental applications. Inspired by the biological mechanisms of bone-forming cells, we develop a synthetic yeast platform osteoyeast, which uses enzymes to break down urea and increase the pH of the surrounding environment. This triggers the yeast vacuoles to accumulate calcium and phosphate as amorphous calcium phosphate, which is then secreted in vesicles and crystallized into HAp. We achieve HAp production at titers exceeding 1 g/L directly from urine. Techno-economic analysis demonstrates that this process offers clear economic and environmental advantages, making it a compelling strategy for high-value resource recovery from human waste.

PMID:40328834 | DOI:10.1038/s41467-025-59416-8

Sci Rep. 2025 May 6;15(1):15801. doi: 10.1038/s41598-025-00476-7.

ABSTRACT

Fusion proteins combining TNF-related apoptosis inducing ligand (TRAIL) and antibody building blocks have emerged as a strategy for the targeted treatment of cancer cells. Using a single-chain derivative of homotrimeric TRAIL (scTRAIL), several targeted and non-targeted scTRAIL fusion proteins of varying geometries and valencies for TRAIL receptors and target antigens, all comprising an Fc region, were generated. These fusion proteins comprised either 1 or 2 scTRAIL units, i.e. are tri- or hexavalent for TRAIL receptors and in the targeted versions, 1 or 2 binding sites for EGFR. These fusion proteins were analyzed for cell binding and cell death induction using the EGFR-expressing colorectal cancer cell lines Colo205 and HCT116. In line with previous findings, all fusion proteins that were hexavalent for TRAIL receptors exhibited a strongly increased cell killing activity compared to the trivalent ones. Interestingly, the fusion proteins comprising one scTRAIL unit, did not benefit from targeting to EGFR. In contrast, the hexavalent scTRAIL fusion proteins further benefited from EGFR targeting, resulting in an approximately 6- to 30-fold increase in cell killing. In summary, this study shed further light on the influence of geometry and valency of TRAIL fusion proteins and confirmed IgG-scTRAIL fusion proteins as highly potent cell death inducers.

PMID:40328809 | DOI:10.1038/s41598-025-00476-7

Signal Transduct Target Ther. 2025 May 7;10(1):148. doi: 10.1038/s41392-025-02232-9.

NO ABSTRACT

PMID:40328772 | DOI:10.1038/s41392-025-02232-9

Nat Commun. 2025 May 7;16(1):4223. doi: 10.1038/s41467-025-59496-6.

ABSTRACT

Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively test proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. We find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.

PMID:40328749 | DOI:10.1038/s41467-025-59496-6

Nat Commun. 2025 May 6;16(1):4214. doi: 10.1038/s41467-025-58966-1.

ABSTRACT

Metabolic reprogramming of amino acids represents a vulnerability in cancer cells, yet the mechanisms underlying serine metabolism in acute myeloid leukemia (AML) and leukemia stem/initiating cells (LSCs/LICs) remain unclear. Here, we identify RNA N6-methyladenosine (m6A) modification as a key regulator of serine biosynthesis in AML. Using a CRISPR/Cas9 screen, we find that depletion of m6A regulators IGF2BP3 or METTL14 sensitizes AML cells to serine and glycine (SG) deprivation. IGF2BP3 recognizies m6A on mRNAs of key serine synthesis pathway (SSP) genes (e.g., ATF4, PHGDH, PSAT1), stabilizing these transcripts and sustaining serine production to meet the high metabolic demand of AML cells and LSCs/LICs. IGF2BP3 silencing combined with dietary SG restriction potently inhibits AML in vitro and in vivo, while its deletion spares normal hematopoiesis. Our findings reveal the critical role of m6A modification in the serine metabolic vulnerability of AML and highlight the IGF2BP3/m6A/SSP axis as a promising therapeutic target.

PMID:40328743 | DOI:10.1038/s41467-025-58966-1

Nat Commun. 2025 May 6;16(1):4187. doi: 10.1038/s41467-025-59434-6.

ABSTRACT

Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

PMID:40328741 | DOI:10.1038/s41467-025-59434-6

Biol Rev Camb Philos Soc. 2025 May 6. doi: 10.1111/brv.70030. Online ahead of print.

ABSTRACT

Freshwater biodiversity is the fastest declining part of the global biota, threatened by multiple stressors including habitat loss and fragmentation, climate change, invasive species, water pollution, and abstraction by humans. A multitude of recent agenda-setting publications have pointed out key objectives and goals for addressing this freshwater biodiversity crisis, but important gaps must be overcome to reach ambitious conservation targets. In this perspective, we complement these high-level papers in freshwater conservation by highlighting important gaps in knowledge, governance, and implementation. This gap-oriented approach is designed to facilitate meaningful action by highlighting missing 'pieces' in the conservation process, and their connection to existing and emerging solutions in the literature. We derive 13 overarching gaps from a conference session and informal synthesis of recent literature in freshwater biodiversity conservation to catalyse research, advocacy, and action to meet freshwater goals for the post-2020 Kunming-Montreal Global Biodiversity Framework (GBF). Key gaps include inventory data on global freshwater biodiversity, collating and mobilizing conservation evidence in practice, improving coordination of ecological governance at scale -including within and across catchments-and navigating trade-offs between economic development, resource consumption, and priorities for freshwater biodiversity. Finally, we apply this gap-oriented approach to key language describing GBF goals for freshwater biodiversity conservation, and point out existing and emerging solutions which may help address important gaps. Major themes that address multiple gaps include the use of Nature-based Solutions and Other Effective Area-based Conservation Measures (OECMs), navigation of water management trade-offs between human and environmental needs, co-production of knowledge with Indigenous and local people and other stakeholders, integration of conservation research and action between aquatic and terrestrial ecosystems, and funding and policy mechanisms to facilitate conservation action and support meaningful monitoring of conservation evidence across hydrological scales.

PMID:40328259 | DOI:10.1111/brv.70030

Cell. 2025 May 5:S0092-8674(25)00455-6. doi: 10.1016/j.cell.2025.04.020. Online ahead of print.

ABSTRACT

Degradation of mRNA containing N6-methyladenosine (m6A) is essential for cell growth, differentiation, and stress responses. Here, we show that m6A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m6A on mRNA. We find that m6A is a potent inducer of ribosome stalling, and these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts. We find that the degree of ribosome stalling correlates with m6A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m6A-mediated mRNA degradation. Ribosome stalling and collision at m6A is followed by recruitment of YTHDF m6A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m6A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m6A sensor for beginning m6A-mRNA degradation.

PMID:40328256 | DOI:10.1016/j.cell.2025.04.020

Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2421747122. doi: 10.1073/pnas.2421747122. Epub 2025 May 6.

ABSTRACT

Infiltrating neutrophils are key effector cells in inflammatory bowel disease (IBD) while providing antimicrobial defense and tissue restitution in the intestine. The complexity of neutrophil functions in local environments underscores our limited understanding of how their adaptation in tissues influences disease progression. Here, we demonstrate that neutrophils recruited in murine colitis and infection models, idiopathic IBD, and chronic granulomatous disease-associated IBD undergo extensive transcriptional reprogramming, resulting in the emergence of neutrophil populations that feature unique DUOX2 NADPH oxidase expression. Functional studies utilizing mice with myeloid and neutrophil specific DUOX2 inactivation reveal a vital and dichotomous role for this NADPH oxidase in both colitis and intestinal infection. Niche-directed reprogramming promoted a DUOX2-dependent chemokine and cytokine-rich intestinal environment that amplified and prolonged inflammatory responses, suggesting that selectively suppressing DUOX2 may constitute an anti-inflammatory strategy for IBD treatment. Altering spatiotemporal redox signaling by de novo expression of a ROS-generating enzyme represents an important feature for functional neutrophil diversification in disease, with implications for other neutrophil-driven diseases in specialized niches.

PMID:40327691 | DOI:10.1073/pnas.2421747122

Bioinformatics. 2025 May 6:btaf280. doi: 10.1093/bioinformatics/btaf280. Online ahead of print.

ABSTRACT

MOTIVATION: Boolean networks are popular dynamical models of cellular processes in systems biology. Their attractors model phenotypes that arise from the interplay of key regulatory subcircuits. A succession diagram describes this interplay in a discrete analog of Waddington's epigenetic attractor landscape that allows for fast identification of attractors and attractor control strategies. Efficient computational tools for studying succession diagrams are essential for the understanding of Boolean attractor landscapes and connecting them to their biological functions.

RESULTS: We present a new approach to succession diagram construction for asynchronously updated Boolean networks, implemented in the biologist's Boolean attractor landscape mapper, biobalm. We compare biobalm to similar tools and find a substantial performance increase in succession diagram construction, attractor identification, and attractor control. We perform the most comprehensive comparative analysis to date of the succession diagram structure in experimentally-validated Boolean models of cell processes and random ensembles. We find that random models (including critical Kauffman networks) have relatively small succession diagrams, indicating simple decision structures. In contrast, non-random models from the literature are enriched in extremely large succession diagrams, indicating an abundance of decision points and suggesting the presence of complex Waddington landscapes in nature.

AVAILABILITY AND IMPLEMENTATION: The tool biobalm is available online at https://github.com/jcrozum/biobalm. Further data, scripts for testing, analysis and figure generation are available online at https://github.com/jcrozum/biobalm-analysis and in the reproducibility artefact at https://doi.org/10.5281/zenodo.13854760.

CONTACT AND SUPPLEMENTARY INFORMATION: giang.trinh91@gmail.com (V.G.T.), xpastva@fi.muni.cz (S.P.), jrozum@binghamton.edu (J.C.R.); The Supplementary Text is available online through Bioinformatics.

PMID:40327535 | DOI:10.1093/bioinformatics/btaf280

ACS Synth Biol. 2025 May 6. doi: 10.1021/acssynbio.5c00077. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa elastase is a metalloprotease with significant industrial potential but is challenging to produce due to its pathogenic origin and folding complexities. In this study, we applied rational design to engineer nonfunctional regions of elastase within Saccharomyces cerevisiae, specifically targeting propeptide and signal peptide cleavage sites, and N-glycosylation in the propeptide. This led to the development of several improved elastase variants. Integrating the yeast protein secretory model pcSecYeast with protease production characteristics, a total of 75 targets were identified and validated, comprising both model-predicted and production-feature-based targets. Notably, overexpression of POS5 enhanced protease activity to 2.43-fold that of the control, while knockout of TES1 or VPS10 further optimized production. This work demonstrates the potential of systems biology in creating yeast cell factories for protease production and highlights S. cerevisiae as a versatile host for biotechnological applications.

PMID:40327375 | DOI:10.1021/acssynbio.5c00077

ACS Synth Biol. 2025 May 6. doi: 10.1021/acssynbio.4c00742. Online ahead of print.

ABSTRACT

Historically, studying the development of brain and central nervous system (CNS) tissues has been challenging. Human pluripotent stem cell (hPSC) technology has allowed for the in vitro reconstitution of relevant, early cell trajectories by using small molecules and recombinant proteins to guide differentiation of cells toward relevant brain and CNS phenotypes. However, many of these protocols fail to recapitulate the cell-guided differentiation programs intrinsic to embryonic development, particularly the signaling centers that emerge within the neural tube during brain formation. Located on the ventral end of the neural tube, the floor plate acts as one such signaling center to pattern the dorsal/ventral axis by secreting the morphogen Sonic Hedgehog (SHH). Here, we present a method for cell-guided differentiation using the synthetic Notch (synNotch) receptor platform to regulate SHH production and subsequent cell fate specification. We show that the widely used configuration of the orthogonal synNotch ligand green fluorescent protein (GFP) mounted on a platelet-derived growth factor receptor-β transmembrane chassis does not allow for robust artificial signaling in synNotch-hPSCs ("receivers") cocultured with ligand-presenting hPSCs ("senders"). We discovered that refined designs of membrane-bound GFP-ligand allow for efficient receptor activation in hPSC receivers. A variant of this enhanced synNotch system drives the production of SHH in hPSC sender:hPSC receiver cocultures and gives rise to floor plate-like cell types seen during neural tube development. This revised synNotch platform has the potential to pattern hPSC differentiation programs in synthetic morphogenesis studies designed to uncover key paradigms of human CNS development.

PMID:40327355 | DOI:10.1021/acssynbio.4c00742

Plant Cell Rep. 2025 May 6;44(6):113. doi: 10.1007/s00299-025-03503-z.

ABSTRACT

Cotton plants undergo a drastic transcriptional reprogramming after cotton boll weevil infestation, modulating several defense pathways to cope with the damage. The global demand for cotton fiber continues to rise, but pests and pathogens significantly hinder cotton production, causing substantial losses. Among these, the cotton boll weevil (Anthonomus grandis) is one of the most destructive pests. To investigate the molecular responses of cotton (Gossypium hirsutum) to boll weevil infestation, we evaluated the global gene expression of floral buds using mRNA-seq. Additionally, we analyzed the expression of non-coding RNAs, including microRNAs (miRNAs) and long intergenic non-coding RNAs (lincRNAs). Infestation by cotton boll weevil larvae triggered a rapid and drastic transcriptional reprogramming, with 1,656 and 1.698 genes modulated after two and twelve hours, respectively. Gene ontology enrichment analysis revealed significant regulation of defense-related and developmental processes, including photosynthesis, primary metabolism, and cell organization. Transcription factor families such as ERF, WRKY, GRAS, and NAC were strongly affected, highlighting their roles in coordinating defense responses. The jasmonate pathway showed intensive modulation, alongside secondary metabolite pathways like terpenoids and phenylpropanoids, which contribute to plant defense mechanisms. Non-coding RNAs also played a critical role in the response. We identified 921 unique known and novel miRNAs, with 36 modulated by the infestation, and predicted 98,850 putative lincRNAs, several of which were differentially expressed. Understanding the genetic and molecular mechanisms underlying cotton's defense against boll weevil, particularly during early infestation stages, is vital for developing biotechnological strategies to reduce pest damage. Our findings provide critical insights to enhance cotton resilience against herbivores.

PMID:40327114 | DOI:10.1007/s00299-025-03503-z

J Exp Med. 2025 Aug 4;222(8):e20241133. doi: 10.1084/jem.20241133. Epub 2025 May 6.

ABSTRACT

In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor-exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of ∼216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.

PMID:40327039 | DOI:10.1084/jem.20241133

Elife. 2025 May 6;14:RP101299. doi: 10.7554/eLife.101299.

ABSTRACT

3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here, we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions for an MYC-driven murine liver cancer model. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFβ-SMAD, which is upregulated in 3D culture, specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (Bcor, Kmt2d, Mettl3, and Mettl14) has opposite outcomes in 2D vs. 3D. We further identify a 3D-dependent synthetic lethality with partial loss of Prmt5 due to a reduction of Mtap expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic, and organogenesis signaling dependencies under different cellular settings.

PMID:40326560 | DOI:10.7554/eLife.101299

Anal Chem. 2025 May 6. doi: 10.1021/acs.analchem.5c00390. Online ahead of print.

ABSTRACT

The interpretation of proteomics data often relies on functional enrichment analysis, such as Gene Ontology (GO) enrichment, to uncover the biological functions of proteins, as well as the examination of protein expression patterns across data sets like the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. However, conventional approaches to functional enrichment frequently produce extensive and redundant term lists, complicating interpretation and synthesis. Moreover, the absence of specialized tools tailored to proteomics researchers limits the efficient exploration of protein expression within specific biological contexts. To address these challenges, we developed Ontolomics-P, a user-friendly web-based tool designed to advance proteomics data interpretation. Ontolomics-P integrates topic modeling using latent Dirichlet allocation (LDA) with GO semantic similarity analysis, enabling the consolidation of redundant terms into coherent topics. These topics are further refined and reannotated using the GPT-4o language model, creating a novel topics database that provides precise and interpretable insights into shared biological functions. Additionally, Ontolomics-P incorporates quantitative proteomic data from 10 diverse cancer types archived in the CPTAC database, allowing for a comprehensive exploration of protein expression profiles from a data-driven perspective. Through detailed case studies, we demonstrate the tool's capacity to streamline workflows, simplify interpretation, and provide actionable biological insights. Ontolomics-P represents a significant advancement in proteomics data analysis, offering innovative solutions for functional annotation, quantitative exploration, and visualization, ultimately empowering researchers to accelerate discoveries in systems biology and beyond.

PMID:40326493 | DOI:10.1021/acs.analchem.5c00390