Biology subjects

Sun, Z.

Publications and source records attributed to Sun, Z..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

A Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced Cardiac Remodeling

BACKGROUNDThe observation that diabetic patients always under tight-glycemic control consistently show better cardiovascular disease outcomes compared to patients who transition to tight-glycemic control after prior conventional glycemic control lead to the concept of metabolic memory. Mechanisms such as epigenetics possibly mediate the lasting metabolic memory effects, our understanding of the underlying mechanisms remains limited. Increased cardiac protein posttranslational O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification is implicated in cardiac remodeling observed in diabetes, and our previous work shows chronically elevated cardiomyocyte O-GlcNAc causes adverse cardiac changes. Therefore, the current study hypothesized that transiently increased cardiomyocyte O-GlcNAcylation leads to exacerbated adverse cardiac remodeling after subsequent pressure-overload. METHODS AND RESULTSUsing our previously described inducible cardiomyocyte specific, dominant-negative O-GlcNAcase (dnOGAh) mouse and single transgenic littermate controls (Con), we induced O-GlcNAc levels for 2wk (ON), followed by a 2wk washout (OFF); mice then underwent transverse-aortic constriction (TAC) or Sham surgery. We observed the expected cardiac remodeling in TAC groups, including decreased cardiac function, and increased hypertrophy and fibrosis. Moreover, these pathologic measures were exacerbated in the ON/OFF-TAC vs. Con-TAC mice; additionally, transcriptomic analysis of LV-tissue from each experimental group showed pathways which not only supported our fibrosis, hypertrophy and functional results of exacerbated cardiac remodeling, but also, revealed potential novel molecular pathways underlying this pathologic remodeling. CONCLUSIONSWe observed exacerbated cardiac pathology between ON/OFF-TAC vs. Con-TAC groups supporting the concept of "O-GlcNAc memory" as a component of metabolic memory. Moreover, transcriptomic analysis provides insight into potential molecular pathways underpinning this metabolic/O-GlcNAc memory such as Ccn2/CTGF-driven fibrosis, and/or Nox4-driven oxidative stress. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/657956v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@717ea9org.highwire.dtl.DTLVardef@132bdcaorg.highwire.dtl.DTLVardef@4a2bdaorg.highwire.dtl.DTLVardef@18508d9_HPS_FORMAT_FIGEXP M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIWe provide a novel paradigm to study phenotypic and molecular effects of specific, transiently increased cardiomyocyte O-GlcNAcylation on the heart. C_LIO_LIOur results show exacerbated adverse cardiac remodeling due to transiently increased cardiomyocyte O-GlcNAc with pressure-overload, supporting the concept of "O-GlcNAc memory" as a component of metabolic memory. C_LIO_LITranscriptomic insights show gene expression basis for not only observed exacerbated adverse cardiac remodeling (e.g., hypertrophy, fibrosis, cardiac dysfunction), but also potential molecular pathways that could drive cardiac pathology exacerbation of O-GlcNAc memory. C_LI What are the clinical implications?O_LIThis study supports a concept of "O-GlcNAc memory", where previously increased cardiomyocyte protein O-GlcNAcylation can impact the later development of differential cardiac pathology--like the pathology seen in metabolic memory research. C_LIO_LIThe potential role of O-GlcNAc in mediating metabolic memory will help focus future translational research on this modification and downstream cardiac effects in diabetes. C_LIO_LITranscriptomic profiling of cardiac remodeling in this model provides an investigational roadmap for future molecular and functional studies to identify novel therapeutics that ameliorate heart disease induced by differential metabolic memory. C_LI

molecular biology↗

bioRxiv2025

Advanced adaptive strategies in an ancestral body plan: insights from a 510-Ma-old leptomitid sponge

Sponges have thrived in diverse environmental conditions since the early Cambrian till today. However, little is known about how their adaptive capability and strategies have been shaped throughout evolutionary history. Here, we explore this question based on a new leptomitid sponge fossil from the Cambrian Stage 4. The family Leptomitidae was an abundant sponge group inhabiting Cambrian soft substrates but significantly declined thereafter. The new species exhibits a sophisticated set of morphological characteristics adaptive to a shallow siliciclastic environment, which are unprecedented among leptomitids. These include (1) a robust body wall woven by spirally twisted monaxonic spicules; (2) a thick stub-like root tuft for anchoring; (3) spicules radiating out from the sponge body to prevent clogging and sinking; and (4) the inferred capability to close the osculum against unfavourable stimuli. Nevertheless, the new fossil species maintains a leptomitid body plan which lacks modularity and morphological plasticity, the two common and critical attributes in extant sponges to enhance flexibility and resilience in changing environmental conditions. This juxtaposition of evolutionary innovation and structural conservatism offers a compelling case for further exploration of the evolutionary mechanisms that shaped early sponge lineages.

paleontology↗

bioRxiv2025

Competing Subclones and Fitness Diversity Shape Tumor Evolution Across Cancer Types

Intratumor heterogeneity arises from ongoing somatic evolution complicating cancer diagnosis, prognosis, and treatment. Here we present TEATIME (estimating evolutionary events through single-timepoint sequencing), a novel computational framework that models tumors as mixtures of two competing cell populations: an ancestral clone with baseline fitness and a derived subclone with elevated fitness. Using cross-sectional bulk sequencing data, TEATIME estimates mutation rates, timing of subclone emergence, relative fitness, and number of generations of growth. To quantify intratumor fitness asymmetries, we introduce a novel metric--fitness diversity--which captures the imbalance between competing cell populations and serves as a measure of functional intratumor heterogeneity. Applying TEATIME to 33 tumor types from The Cancer Genome Atlas, we revealed divergent as well as convergent evolutionary patterns. Notably, we found that immune-hot microenvironments constraint subclonal expansion and limit fitness diversity. Moreover, we detected temporal dependencies in mutation acquisition, where early driver mutations in ancestral clones epistatically shape the fitness landscape, predisposing specific subclones to selective advantages. These findings underscore the importance of intratumor competition and tumor-microenvironment interactions in shaping evolutionary trajectories, driving intratumor heterogeneity. Lastly, we demonstrate that TEATIME-derived evolutionary parameters and fitness diversity offer novel prognostic insights across multiple cancer types.

bioinformatics↗

bioRxiv2025

Spatiotemporal transcriptomic analysis during cold ischemic injury to the murine kidney reveals compartment-specific changes

BackgroundKidney transplantation is the preferred treatment strategy for end-stage kidney disease. Deceased donor kidneys usually undergo cold storage until kidney transplantation, leading to cold ischemia injury that may contribute to poor graft outcomes. However, the molecular characterization of potential mechanisms of cold ischemia injury remains incomplete. ResultsTo bridge this knowledge gap, we leveraged the 10x Visium spatial transcriptomic technology to perform full transcriptome profiling of murine kidneys subject to varying durations of cold ischemia typical in a deceased donor kidney transplant setting. We developed a computational workflow to identify and compare spatiotemporal transcriptomic changes that accompany the injury pathophysiology in a tissue compartment-specific manner. We identified proportional enrichment of oxidative phosphorylation (OXPHOS) genes with increasing duration of cold ischemia injury within the oxygen-lean inner medulla region, suggestive of atypical metabolic presentation. This was distinct in cold ischemia injury tissue compared to warm ischemia-reperfusion kidney injury tissue. Spatiotemporal trends were validated by qPCR and immunofluorescence in a larger cohort of mice. We provide an interactive online browser at https://jef.works/CellCarto-ColdIschemia/ to facilitate exploration of our results by the broader scientific and clinical community. ConclusionsAltogether, our spatiotemporal transcriptomic analysis identified coordinated molecular changes within metabolic pathways such as OXPHOS deep within the cold ischemic kidney, highlighting the need for increased attention to the inner medulla and potential opportunities for new insights beyond those available from superficial biopsy-focused tissue examinations.

bioinformatics↗

bioRxiv2025

Intestinal Stem Cells Retain an Epigenetic Memory of Prior Inflammation

Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from IBD patients acquire lasting memory of prior inflammation. To test this, we derived colonic organoids from inflamed and uninflamed regions of the same UC patients and propagated in long-term culture. Chromatin profiling revealed 2,252 accessible regions unique to prior-inflamed (PI) organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, [~]95% of associated genes were not upregulated in PI organoids, indicating a primed state. Upon inflammatory or injury re-challenge, PI organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program. Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. While this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.

molecular biology↗

bioRxiv2025

In vivo CRISPR screening identifies NF1/RASA1/TP53 co-mutations and downstream MEK signaling as a common key mechanism of sinonasal tumorigenesis

Genomic alterations driving tumorigenesis in sinonasal malignancies remain largely unexplored. Here, we perform an in vivo loss-of-function screen using a pooled custom single-guide library delivered to the sinonasal cavity by adeno-associated virus vector to identify cancer driver genes across diverse sinonasal malignancies. This approach yielded sinonasal malignancies with diverse histologies, including sinonasal squamous cell carcinoma, adenocarcinoma, poorly differentiated sinonasal carcinoma, and sinonasal neuroendocrine tumors characteristic of olfactory neuroblastoma. Surprisingly, rather than observing distinct sgRNA profiles across sinonasal tumor subtypes, common recurrent mutations were identified in Nf1 (79%), Rasa1 (74%), and Trp53 (68%) across malignancies with distinct histologies. Utilizing an orthogonal approach, we confirmed that Nf1/Trp53 were required for sinonasal tumorigenesis. Given that loss-of-function in NF1 and RASA1 may lead to increased Ras activity and downstream MEK signaling, we tested small molecule targeting of the RAS-MAPK pathway in sinonasal malignancies. Indeed, both tumor cell lines derived from our loss-of-function approach as well as from human sinonasal malignancies displayed significant sensitivity to MEK inhibition in standard in vitro culture and organoid models. These findings demonstrate that loss of NF1 and RASA1-mediated Ras-GAP activity leads to Ras activation and downstream MEK signaling which is a potential common target throughout major sinonasal tumor subtypes.

cancer biology↗

bioRxiv2025

Deep Blood Proteomics Identifies over 12,000 Proteins Providing Valuable Information about the State of the Human Body

Blood is a valuable resource for clinical research, offering insight into physiological and pathological states. However, the specific proteins detectable in blood and the optimal proteomic methods for their detection have not been rigorously investigated and documented. To address this, we conducted various blood proteomic strategies, including directly blood proteomic analysis, high-abundance protein depletion, low-abundance protein enrichment, and extracellular vesicle enrichment using data-independent acquisition or targeted proteomics. These approaches identified 11,679 protein groups in plasma from healthy individuals. In 136 pancreatic ductal adenocarcinoma whole blood samples, 6,956 protein groups were found, including 678 not seen in healthy samples, expanding the total to 12,357 blood proteins. This represents the most comprehensive blood proteome to date. To support broader access and analysis, we developed the Human Blood Proteome (HuBP) database, detailing protein detectability, abundance, and reproducibility across workflows, sample types, and disease contexts.

systems biology↗

bioRxiv2025

AMPK activation prevents HCC development through inhibition of HNF4a activity

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality and is largely driven by metabolic disorders such as obesity and Type 2 Diabetes. The AMP-activated protein kinase (AMPK) is a master regulator of metabolism, coordinating glucose and lipid metabolism, and its activation has been proposed as a therapeutic strategy for treating metabolic disorders. However, while AMPK activity has been reported to be downregulated in HCC, the precise role of AMPK in HCC development has not been clearly delineated. Here, we investigated the ability of AMPK activation to prevent HCC development using genetic models and specific allosteric AMPK activators. By leveraging a constitutively active AMPK transgenic mouse model and a pharmacological AMPK activator, we were able to elucidate the direct effects of AMPK activation on HCC development and progression. We observed that AMPK activation significantly reduced tumor formation in both diethylnitrosamine (DEN)-induced and streptozocin-induced (STAM) models of HCC. Our findings further implicate bile acid metabolism and hepatic nuclear factor alpha (HNF4) signaling in the mechanism of AMPK-dependent HCC prevention. These findings provide mechanistic insights into AMPK biology and highlight the potential of AMPK as a therapeutic target, emphasizing the intricate interplay between metabolic dysregulation and cancer development.

cancer biology↗

bioRxiv2025

Systematic Background Selection for Enhanced Contrastive Dimension Reduction

Contrastive dimension reduction enhances the analysis of high-dimensional data by generating target-specific low-dimensional representations relative to a background. Emerging methods for contrastive dimension reduction have demonstrated their utility in extracting target-specific signals across domains involving high-dimensional observations, including genomics, transcriptomics, and pattern recognition. However, even though choosing an appropriate background is critical to the success of contrastive dimension reduction, no established criterion currently exists for selecting such backgrounds. To address this gap, we introduce BasCoD, a novel testing framework grounded in the spectral theory of subspace inclusion, to enable rigorous evaluation and optimal selection of backgrounds. Extensive application of BasCoD across diverse single-cell datasets demonstrates its effectiveness in systematically identifying suitable backgrounds, thereby significantly improving the contrast and interpretability of the derived target representations. We further illustrate how BasCoD can facilitate design of appropriate backgrounds in large-scale single cell experiments under heterogeneous conditions.

genomics↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

Aneuploidy, the gain or loss of chromosomes, is prevalent in both normal and disease conditions, however, experimental approaches to engineer and study aneuploidy remain limited, leaving its functional significance under-characterized. Here, we present CRISPR-Taiji (CRISPRt), an efficient method for inducing chromosome-specific mis-segregation and aneuploidy generation across all 24 human chromosomes via dead Cas9 (dCas9)-induced centromeric chromatin relaxation. Using CRISPRt with scRNA-seq, we generated the first comprehensive transcriptomic alteration landscape of nearly all autosomal aneuploidies at chromosome-arm resolution. This genotype-phenotype map provides causal evidence linking recurrent aneuploidies in clear cell renal cell carcinoma (ccRCC) to molecular and clinical phenotypes observed in patient tumors. Notably, chromosome 3(p) loss, the ccRCC initiating event, specifically drives strong interferon signaling activation, offering novel insights into ccRCC tumorigenesis and immune modulation. Overall, we establish CRISPRt as a simple, efficient and scalable approach for chromosome-specific aneuploidy engineering and characterization in preclinical models to advance aneuploidy research across diverse biological contexts.

genomics↗

bioRxiv2025

CREB5 promotes immunotherapy resistance via tumor-intrinsic collagenmatrix deposition

Treatment with immune checkpoint inhibitors induces remarkable clinical responses in several cancer types. However, most cancer patients fail to respond to immunotherapy, and patients who initially respond often exhibit acquired resistance. Understanding the universe of immune evasion strategies will enable design of more effective immunotherapies. Here, we identify genes that drive immune evasion using genome-scale in vivo CRISPR gain-of-function screens in tumors treated with anti-PD-1 antibodies and found that the transcription factor CREB5 drives immune checkpoint blockade resistance. Using transcriptional profiling and functional studies, we show that CREB5 promotes a mesenchymal-like phenotype in melanoma characterized by upregulation of extracellular matrix genes including collagen and collagen-stabilizing factors. Using engineered tumor models and knockout mice, we found that immunotherapy resistance is functionally mediated by tumor-intrinsic collagen deposition. Collagen is the major ligand for the inhibitory receptor LAIR1, broadly expressed on T cells, B cells, NK cells, and myeloid cells. Deletion of LAIR1 in mice or overexpression of the decoy receptor LAIR2 in tumors abrogated the resistance induced by CREB5 overexpression, demonstrating that collagen-LAIR1 inhibitory signaling drives resistance to immune checkpoint inhibitors. These observations define a transcriptional program that remodels the tumor microenvironment to promote immunotherapy resistance via extracellular matrix deposition and indicates that targeting this pathway may enhance immunotherapy efficacy. One-Sentence Summary: In vivo gain-of-function screening in immunotherapy-treated mice reveals a transcription factor, Creb5, that drives the mesenchymal state in melanoma and facilitates immune escape by promoting tumor-intrinsic collagen matrix deposition.

cancer biology↗

bioRxiv2025

LPS/TLR4-Activating Exosomes from M1-Polarized Avian Macrophages Enhances IBV Vaccine-Induced Protective Immunity in Chickens

Infectious bronchitis virus (IBV) presents a substantial economic burden to poultry production due to extensive serotypic diversity and limited cross-protection afforded by conventional vaccines. This study evaluated exosomes derived from M1-polarized chicken macrophages (HD11M1-exo) as a novel adjuvant for IBV vaccination. HD11M1-exo, isolated from LPS-activated HD11 macrophages via ultracentrifugation, demonstrated significant immunomodulatory properties across multiple experimental systems. In vitro analyses revealed HD11M1-exo enhanced macrophage phagocytosis and cellular immune activation via the LPS/TLR4 signaling pathway. In embryonated eggs, HD11M1-exo pre-treatment induced TNF- upregulation, enhanced viral resistance, and reduced pathological damage. In chickens, HD11M1-exo administration elevated CD80/CD86 and TGF-{beta}4 expression in respiratory tissues and increased secretory IgA in lacrimal fluid. When combined with H120 vaccine, HD11M1-exo significantly augmented both humoral immunity (elevated serum IgY and mucosal IgA) and cellular responses (increased CD80/CD86 expression), surpassing commercial adjuvants in efficacy. Following viral challenge, HD11M1-exo+H120 immunized chickens exhibited significantly reduced viral loads and attenuated histopathology compared to controls. These data collectively suggest that exosome-based formulations may serve as effective adjuvants for enhancing poultry vaccine immunogenicity and protective efficacy.

immunology↗

bioRxiv2025

Human visual grouping based on within- and cross-area temporal correlations

Perceptual organization in the human visual system involves neural mechanisms that spatially group and segment image areas based on local feature similarities, such as the temporal correlation of luminance changes. Successful segmentation models in computer vision, including graph-based algorithms and vision transformer, leverage similarity computations across all elements in an image, suggest that effective similarity-based grouping should rely on a global computational process. However, whether human vision employs a similarly global computation remains unclear due to the absence of appropriate methods for manipulating similarity matrices across multiple elements within a stimulus. To investigate how "temporal similarity structures" influence human visual segmentation, we developed a stimulus generation algorithm based on Vision Transformer. This algorithm independently controls within-area and cross-area similarities by adjusting the temporal correlation of luminance, color, and spatial phase attributes. To assess human segmentation performance with these generated texture stimuli, participants completed a temporal two-alternative forced-choice task, identifying which of two intervals contained a segmentable texture. The results showed that segmentation performance is significantly influenced by the configuration of both within- and cross-correlation across the elements, regardless of attribute type. Furthermore, human performance is closely aligned with predictions from a graph-based computationalmodel, suggesting that human texture segmentation can be approximated by a global computational process that optimally integrates pairwise similarities across multiple elements. Author SummaryHow does the human visual system use temporal information to segment objects in a dynamic scene? When observing ever-changing environments, our brains must determine which regions belong to the same object and which are distinct. However, the mechanisms underlying this process remain poorly understood. In this study, we investigate how "temporal similarity structures"--patterns of correlation over time--affect visual segmentation. We developed a novel method for generating dynamic stimuli with precisely controlled temporal similarity and systematically tested how within-area and cross-area correlations influence segmentation. Participants performed a task in which they identified segmentable textures, and the results showed that segmentation performance improves when regions exhibit strong internal consistency but lower similarity with adjacent regions. Our findings revealed that human visual segmentation relies on a global computational mechanism that integrates temporal similarity cues to distinguish visual structures. Additionally, our stimulus generation framework provides a powerful tool for future research on perceptual organization and mid-level vision.

neuroscience↗

bioRxiv2025

Next-Generation saRNA Platforms: Systematic Screening and Engineering Enhances Superior Protein Expression and Organ-Specific Targeting for RNA Therapeutics

Self-amplifying RNA (saRNA), derived from alphaviruses, encodes nonstructural proteins (NSP1-4) that form a replicase complex, enabling prolonged and amplified protein expression at lower doses than conventional mRNA. However, its high immunogenicity and limited replication efficiency require optimization for improved protein expression. Here, we systematically optimized a widely used Venezuelan Equine Encephalitis Virus (VEEV)-based saRNA by refining its capping structure, nucleotide modifications, polyA tail length, and regulatory elements, achieving over 10-fold enhancement in protein expression compared to the wild-type. Additionally, we screened 28 alphavirus-derived saRNA constructs in vitro, selecting the top 3 candidates Everglades virus (EVEV), Mosso das Pedras virus (MDPV), and Rio Negro virus (RNV) for in vivo evaluation using SM102 lipid nanoparticle (LNP) formulations and luciferase reporters. These optimized saRNAs demonstrated sustained expression and distinct extrahepatic tissue-specific biodistribution, notably high spleen targeting compared to conventional mRNA. Such organ-specific expression profiles present novel strategies for targeted RNA therapeutics, and further integration with advanced delivery technologies could enhance the precision, efficacy, and therapeutic potential of mRNA-based treatments. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/644708v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1eed9bdorg.highwire.dtl.DTLVardef@192815org.highwire.dtl.DTLVardef@196a8e9org.highwire.dtl.DTLVardef@2b6e53_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOTOC figureC_FLOATNO C_FIG

molecular biology↗

bioRxiv2025

Genomic and Transcriptomic Signatures of SETD1A Disruption in Human Excitatory Neuron Development and Psychiatric Disease Risk

Genetic disruption of SETD1A markedly increases the risk for schizophrenia. To elucidate the underlying mechanisms, we generated isogenic organoid models of the developing human cerebral cortex harboring a SETD1A loss-of-function schizophrenia risk mutation. Employing chromatin profiling combined with RNA sequencing, we identified high-confidence SETD1A target genes, analyzed the impact of the mutation on SETD1A binding and transcriptional regulation and validated key findings with orthogonal approaches. Disruption of SETD1A function disturbs the finely tuned temporal gene expression in the excitatory neuron lineage, yielding an aberrant transcriptional program that compromises key regulatory and metabolic pathways essential for neurodevelopmental transitions. Although overall SETD1A binding remains unchanged in mutant neurons, we identified localized alterations in SETD1A binding that correlate with shifts in H3K4me3 levels and gene expression. These changes are enriched at enhancer regions, suggesting that enhancer-regulated genes are especially vulnerable to SETD1A reduction. Notably, target genes with enhancer-bound SETD1A are primarily linked to neuronal functions while those with promoter-bound SETD1A are enriched for basic cellular functions. By mapping the SETD1A binding landscape in excitatory neurons of the human fetal frontal cortex and integrating multimodal neuroimaging and genetic datasets, we demonstrate that the genomic context of SETD1A binding differentially correlates with macroscale brain organization and establish a link between SETD1A-bound enhancers, schizophrenia-associated brain alterations and genetic susceptibility. Our study advances our understanding of the role of SETD1A binding patterns in schizophrenia pathogenesis, offering insights that may guide future therapeutic strategies.

neuroscience↗

bioRxiv2025

Peptide abundance correlations in metaproteomics enhance taxonomic and functional analysis of the human gut microbiome

Mass spectrometry (MS)-based proteomics is widely used for quantitative protein profiling and has become a powerful tool for studying protein interactions. However, most current research focuses on single-species proteomics to study protein interactions. Protein interactions within more complex microbiomes, composed of 100s of bacterial species, remain largely unexplored. The human gut microbiome, closely linked to human health and disease, has become a key area of study using metaproteomics. Yet, due to the complexity of the microbiome, the interactions between gut microbes and their host remain largely unknown. In this study, we analyzed peptide abundance correlations within a metaproteomics dataset derived from in vitro cultured human gut microbiomes subjected to various drug treatments. Our analysis revealed that peptides from the same protein or taxon exhibited correlated abundance changes. By using t-SNE for visualization, we generated a peptide correlation map in which peptides from the same taxon formed distinct clusters. Furthermore, peptide abundance correlations enabled genome-level taxonomic assignments for a greater number of peptides. In single-species subsets of the dataset, peptide correlation networks constructed using taxon-based normalized peptide abundance (TNPA) linked peptides from functionally related proteins. These networks also provided insights into the potential functions of previously uncharacterized proteins. Altogether, our study demonstrates that analyzing peptide abundance correlations enhances both taxonomic and functional analyses in human gut metaproteomics research.

microbiology↗

bioRxiv2025

Enzyme Co-Scientist: Harnessing Large Language Models for Enzyme Kinetic Data Extraction from Literature

The extraction of molecular annotations from scientific literature is critical for advancing data-driven research. However, traditional methods, which primarily rely on human curation, are labor-intensive and error-prone. Here, we present an LLM-based agentic workflow that enables automatic and efficient data extraction from literature with high accuracy. As a demonstration, our workflow successfully delivers a dataset containing over 91,000 enzyme kinetics entries from around 3,500 papers. It achieves an average F1 score above 0.9 on expert-annotated subsets of protein enzymes and can be extended to the ribozyme domain in fewer than 3 days at less than $90. This method opens up new avenues for accelerating the pace of scientific research.

biochemistry↗