Biology subjects

Xie, Y.

Publications and source records attributed to Xie, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

The common evolution of fungicide persistence in cryptococcosis patients

Fungicide persistence, the ability of dormant fungal cells to survive lethal drug exposure, undermines treatment efficacy, yet its clinical evolution remains largely unexplored. We assembled a nationwide collection of clinical Cryptococcus neoformans isolates from China and revealed extensive inter strain variation in amphotericin B (AmB) persistence. This variation can arise from common evolutionary events in patients, generating previously undescribed high persistence cryptococcal variants refractory to AmB clearance. Genome wide fitness landscape analysis shows that persistence associated mutations generally impose minimal fitness costs, facilitating persistence evolution even in fungistatic resistant and hypervirulent genetic backgrounds. Machine learning identified deficient ACO2 expression as a key predictor of high persistence clinical isolates. ACO2 deficiency reproduces the high persistence phenotype by promoting POPC accumulation, which competes with AmB for its target. Moreover, the clinical stage antifungal T-2307 effectively eliminates high persistence strains across diverse genetic backgrounds. Collectively, our findings unveil common evolution of fungicide persistence in cryptococcosis patients, representing a previously overlooked clinical concern.

microbiology↗

bioRxiv2026

Automating scientific annotations for open transcriptomic profiles via multi-stage agents

Public transcriptomic repositories contain millions of samples, yet their large-scale reuse is hindered by heterogeneous and inconsistently reported metadata. In the Gene Expression Omnibus (GEO), key biological information is often distributed across study- and sample-level records, requiring context-dependent interpretation. Here we present GEOMeta, a large language model (LLM)-based multi-stage workflow with task-specialized agents for automated GEO metadata curation. The pipeline separates metadata retrieval, task-specific information extraction, field standardization, ontology mapping and quality control. Using GEOMeta, we generated standardized annotations for approximately 600,000 human bulk RNA-seq samples. To demonstrate its utility, we benchmarked transcriptome representation models for predicting sex, age, tissue and disease from transcriptome embeddings. We further prospectively annotated newly submitted GEO studies and evaluated 22 frontier LLMs. Recent open-source Flash models achieved annotation quality comparable to leading reasoning models while reducing costs by an order of magnitude. GEOMeta provides a scalable resource and reproducible framework for metadata curation.

bioinformatics↗

bioRxiv2026

Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression

Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

cancer biology↗

bioRxiv2026

An architectural switch in the evolution of the γ-tubulin ring complex

Canonical microtubules contain 13-protofilaments and are templated by the {gamma}-tubulin ring complex ({gamma}-TuRC). However, some eukaryotes assemble non-canonical microtubules, like the 11-protofilament structures found in Caenorhabditis elegans. How {gamma}-TuRCs adapt to template alternative microtubule geometries is unclear. Here, we present the cryo-electron microscopy structure of the C. elegans {gamma}-TuRC ({gamma}-TuRCCe), revealing a cone-shaped assembly consistent with an 11-protofilament template. While the complex incorporates the conserved subunits actin, GCP2 and GCP3, {gamma}-TuRCCe replaces GCP4-6 with a divergent 4-spoked assembly containing additional copies of GCP2 and the nematode-specific proteins GTAP-1 and GTAP-2. Structures of nucleotide-free {gamma}-TuRCCe subcomplexes reveal partial {gamma}-tubulin unfolding, suggesting nucleotide binding stabilizes eukaryotic tubulins. Remarkably, reconstituted 4-spoked assemblies can multimerize into [~]13-fold symmetric microtubule nucleation templates in vitro, contrasting with the native complexs 11-protofilament architecture. Our work defines the structural blueprint of an 11-protofilament microtubule template and shows how divergent {gamma}-tubulin components are repurposed to accommodate non-canonical microtubule lattices.

biochemistry↗

bioRxiv2026

Multidimensional atlas of RNA-regulated proteins revealed by RNA-dependent thermal proteome profiling

RNA and proteins interact pervasively in cellular processes, yet the functional relevance of most RNA-binding proteins remains unknown. To address this, we developed RNA-dependent thermal proteome profiling (RTPP), a method that identifies RNA-regulated proteins (RRPs) by detecting changes in a proteins structural stability upon RNA binding, without requiring crosslinking or enrichment. Applying RTPP in HEK293T cells revealed 1,664 RRPs, including 257 previously undetected RNA-binding "orphans". One such orphan, SGK3, binds the lncRNA CASC15, facilitating its PtdIns(3)P binding, endosomal recruitment and kinase activity. We further generated a tissue-specific RRP atlas, identifying interactions unique to particular organs, including hippocampus-specific RRPs dysregulated in Alzheimers disease. Integrating RTPP with proximity labeling resolved RNA-binding heterogeneities across subcellular compartments. Live-cell RNase treatment also uncovered proteins associated with cell surface RNA, revealing that RO60 form nanoscale clusters with glycoRNA. RTPP provides a powerful approach to decipher functional RNA-protein interactions across multiple biological dimensions.

molecular biology↗

bioRxiv2026

Spatial Topology Reveals Biologically Distinct Recurrent Motifs in Colorectal Cancer

Most spatial transcriptomic analyses of solid tumors focus on individual cell states or single-sample spatial domains rather than on recurrent multicellular tissue architectures shared across patients, and typically depend on predefined cell-type annotations or compartment definitions. We developed STORM (Spatial Topology analysis of Recurrent Motifs), an unsupervised graph-attention variational autoencoder that learns recurrent spatial motifs directly from cell-level graph structure and molecular profiles without cell-type labels, manual annotation, or predefined compartments. We applied to 32 Xenium sections from 16 patients with paired early-onset (EOCRC) and average-onset (AOCRC) colorectal cancer, STORM identified 10 recurrent motifs that self-organized into tumor-parenchymal, stromal, and immune macro-compartments. Among these, the Desmoplastic Fibrotic Barrier (DFB) motif, a CAF- and ECM-rich boundary architecture, was associated with restricted CD8+ T-cell geodesic access to tumor cores independently of CD8+ abundance, as demonstrated by abundance-normalized neighborhood enrichment statistics and within-sample mixed-effects models. EOCRC selectively amplified this barrier-exclusion architecture, exhibiting tighter tumor parenchyma, denser DFB shells, and a DFB-specific ECM activation program that yielded an age-specific prognostic signature in TCGA-COAD. Translation of motif macro-classes to H&E images via a Vision Transformer classifier produced an image-derived DFB-barrier composite that predicted overall survival in advanced-stage TCGA colorectal cancer. STORM provides an annotation-free framework for discovering recurrent spatial motifs and identifies a fibroblast barrier architecture whose topological association with immune exclusion is independent of effector abundance, amplified in early-onset disease, and translatable to a deployable pathology-based prognostic biomarker.

bioinformatics↗

bioRxiv2026

Spatial and functional mapping of the human pancreas reveals endocrine and exocrine cell states in health and metabolic disease

The human pancreas contains diverse endocrine and exocrine cell populations whose spatial organization is essential for tissue physiology. While single-cell and spatial transcriptomics revealed molecular heterogeneity across pancreatic cell types, linking these states to physiological activity in situ has remained challenging. Here, we combined single-nucleus RNA sequencing, spatial transcriptomics, and functional calcium imaging across pancreatic samples in health and metabolic disease. We identified heterogeneous endocrine and exocrine cell states associated with obesity and diabetes, including inflammatory remodeling of acinar and ductal populations. To directly couple tissue physiology with molecular state, we developed Slice-seq, which integrates calcium imaging with spatial transcriptomics in acute pancreatic slices. Slice-seq linked local endocrine composition and transcriptional programs with {beta} cell activity and identified extra-islet {beta} cells with reduced glucose responsiveness and mitochondrial oxidative metabolism. Together, our study provides a framework for linking pancreatic cell states to tissue organization and physiological activity in health and disease.

genomics↗

bioRxiv2026

Particle size determines mucociliary transport mechanisms in normal and cystic fibrosis airways

A wide spectrum of microparticles is inhaled with each breath, deposited on airway surfaces, entrapped in the mucus, and removed by mucociliary transport (MCT). However, the influence of particle size on MCT remains largely unknown. Here, we investigated the MCT of microparticles with a trachea-on-a-chip method that integrates a micro-machined device with a trachea explant from newborn pigs. This method preserves airway structures for mucus secretion and cilia beating (e.g., airway surface epithelia and submucosal glands), maintains physiological air-liquid-interface on the airway surface, and allows tracks motion of microparticles with high resolution. Using this method, we found that, in normal airways, 6 {micro}m polystyrene particles clear rapidly, whereas 102 {micro}m particles clear slower and require mucus strands for motion. In cystic fibrosis (CF) airways, MCT of microparticles reduces, but particle size-dependence persists. Methacholine increases particle motion in normal airways, but not in CF airways. These findings suggest two distinct MCT processes, in which large particles rely on mucus strands for clearance, small particles can be cleared independent of mucus strands, and CF disrupts both. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/735890v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@3e3026org.highwire.dtl.DTLVardef@cb11fdorg.highwire.dtl.DTLVardef@a28a3org.highwire.dtl.DTLVardef@f1f1a9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

bioengineering↗

bioRxiv2026

Structural assemblies for an RNA world

Protein homo-oligomerization widely generates symmetric assemblies for encapsulation and scaffolding. Conversely, natural RNA quaternary structures appear limited, with known RNA-only multimers predominantly forming dimers or dihedral assemblies from long transcripts. Whether short RNAs can access broader higher-order assembly space has remained unclear. Here, using cryo-EM, we show that RNAs under 200 nucleotides form three distinct structural classes: a 60-subunit viral-capsid-like icosahedron, non-caged oligomers including a trimer and a strand-exchanged dimer, and a continuous filament assembled from a 57-nucleotide RNA. These structures demonstrate that assembly complexity does not simply scale with RNA length; compact RNAs can specify architectures traditionally associated with proteins. Our findings broaden the known RNA quaternary repertoire, strengthen the structural plausibility of higher-order organization in an RNA world, and establish foundational reference architectures to guide future RNA-based self-assembling nanoparticle design. HighlightsO_LIShort RNAs reveal protein-like assembly principles for an RNA world C_LIO_LIThe first natural RNA-only T=1 icosahedral cage is a viral-capsid-like 60-mer C_LIO_LICompact RNA-RNA interfaces encode global curvature, valency and propagation C_LIO_LIRNA motifs assemble into closed cages, finite oligomers and extended filaments C_LI

evolutionary biology↗

bioRxiv2026

Intrinsically disordered N-terminal regions suppress cotranslational protein degradation

Intrinsically disordered regions (IDRs) of proteins are thought to be inherently sensitive to proteolysis and considered one of the key components constituting an efficient degron. Here we report that IDRs can also suppress protein degradation. Our recent study showed that yeast ribosomal proteins, while posttranslationally stable, are subject to cotranslational protein degradation (CTPD). In mapping the degron responsible for CTPD of ribosomal protein Rpl8A, we found that its N-terminal IDR suppresses CTPD, whereas the adjacent structured domain acts as a degron. We further assessed the N-terminal IDRs of 9 other yeast proteins and found that they all inhibit CTPD. These results suggest that suppression of CTPD is likely a generic function of N-terminal IDRs. Moreover, we showed that the N-terminal IDR of human ribosomal protein hRpl7A also functions as a stabilizer against CTPD in human cells. When transplanted to the N-terminus of cystic fibrosis transmembrane conductance regulator (CFTR), the N-terminal IDR of hRpl7A reduces CTPD of CFTR by more than 80%. Thus, the stabilizer function of N-terminal IDRs is conserved from yeast to human. Using mass spectrometry, we demonstrated that HSP70 chaperone proteins Ssa and Ssb bind to the N-terminal IDR of Rpl8A. These data suggest that N-terminal IDRs may inhibit CTPD through recruiting HSP70 chaperone proteins to nascent chains, thereby facilitating cotranslational folding. Our study unveils a new role for IDRs in suppressing CTPD.

biochemistry↗

bioRxiv2026

M6A-modified circEZH2 Protects Endothelial Cells from Senescence and Suppresses Atherosclerosis by Stabilizing ZNF326

BACKGROUNDEndothelial cell senescence induces endothelial dysfunction, thereby contributing to atherosclerosis progression. Circular RNAs (circRNAs) play diverse roles in multiple physiological and pathological processes. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic RNAs and dynamically regulates RNA fate and function. However, the functions and therapeutic potential of m6A-modified circRNAs in endothelial cell senescence remain unknown. METHODSm6A-modified circRNAs associated with endothelial cell senescence were screened by circRNA expression and m6A-circRNA microarray profiling of endothelial cells and mouse aortic intima. circEZH2 expression was validated in endothelial cells, vascular tissues, and human atherosclerotic plaques by RT-qPCR, and RNA fluorescence in situ hybridization. The role of circEZH2 in endothelial senescence and atherosclerosis was assessed in vitro and in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, and rescue experiments were used to define the underlying mechanism. RESULTSWe identified A novel m6A-modified circRNA, circEZH2, that was downregulated in the aged aortic intima and advanced plaques. CircEZH2 was stabilized by m6A reader IGF2BP2. Endothelial cell-specific overexpression of circEZH2 delayed senescence and suppressed atherosclerosis progression. At the cellular level, circEZH2 overexpression delayed senescence, decreased p53/p21 levels and increased angiogenic activity of endothelial cells, while circEZH2 knockdown exhibited the opposite effect. Mechanistically, circEZH2 functions as a scaffold to promote USP37-mediated deubiquitination, thereby stabilizing ZNF326. Moreover, endothelial cell-specific knockdown of ZNF326 counteracts the anti-senescent and anti-atherosclerotic effects mediated by circEZH2 overexpression. CONCLUSIONSIn summary, the present study identifies circEZH2 as a novel suppressor of endothelial cell senescence, highlighting its potential as a therapeutic target for age-related atherosclerosis. GRAPHIC ABSTRACTA graphic abstract is available for this article. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/730538v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@d3a586org.highwire.dtl.DTLVardef@1180c1forg.highwire.dtl.DTLVardef@1c3d832org.highwire.dtl.DTLVardef@a6d424_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Schematic model of m6A-modified circEZH2 regulation in endothelial cell senescence and atherosclerosis. In young endothelial cells, IGF2BP2 is highly expressed and recognizes m6A-modified circEZH2, thereby maintaining its RNA stability. CircEZH2 stabilizes ZNF326 protein through USP37-mediated deubiquitination, which leads to suppression of p21 and p53, delays endothelial cell senescence, ameliorates endothelial dysfunction, and ultimately suppresses the progression of atherosclerosis. C_FIG What Are the Clinical Implications?This study identifies circEZH2 as a novel m6A-modified circular RNA that is reduced in the aged aortic intima and in endothelial cells within advanced atherosclerotic plaques. Endothelial circEZH2 overexpression delays endothelial cell senescence, preserves endothelial function, and suppresses atherosclerotic lesion formation, supporting an important role for circEZH2 in vascular aging-associated atherosclerosis. Mechanistically, circEZH2 acts as a scaffold to enhance USP37-mediated deubiquitination and stabilization of ZNF326, while endothelial ZNF326 knockdown counteracts the anti-senescent and anti-atherosclerotic effects of circEZH2. These findings reveal the circEZH2-ZNF326 axis as a previously unrecognized mechanism regulating endothelial senescence and atherosclerosis progression. Our work supports the potential of circEZH2-based gene therapy as a novel therapeutic approach for atherosclerosis.

cell biology↗

bioRxiv2026

The engulfment receptor CED-1/MEGF10 activates the GPCR LAT-1/ADGRL3 for apoptotic cell degradation

Efferocytosis, the clearance of apoptotic cells, is crucial for tissue homeostasis, inflammation suppression, and repair. While several G protein-coupled receptors (GPCRs) are involved, the broader role of GPCRs in efferocytosis remains unexplored. Through a genome-wide RNAi screen in Caenorhabditis elegans, we identified the adhesion GPCR LAT-1 as a key regulator of apoptotic cell degradation through the promotion of phagosome maturation. Our secondary RNAi scrween for transcriptional regulators revealed that the transcription factor AST-1 acts downstream of LAT-1 to mediate apoptotic cell degradation. We show that the engulfment receptor CED-1 functions as a ligand for LAT-1, activating a Gs protein/adenylyl cyclase/PKA/AST-1 signaling cascade and inducing the transcription of vps-34 and piki-1, which encode phosphatidylinositol 3-kinases essential for PtdIns3P generation on phagosomes. This pathway maintains appropriate VPS-34 and PIKI-1 levels for efficient efferocytosis. Notably, LAT-1 is evolutionarily conserved, with homologs in Drosophila (CIRL) and mammals (ADGRL3) performing similar functions. These findings reveal a conserved CED-1/MEGF10-LAT-1/ADGRL3 axis that orchestrates apoptotic cell clearance via a novel transcriptional regulatory pathway, providing new insight into the molecular mechanisms underlying tissue homeostasis and diseases associated with defective efferocytosis, including autoimmunity and neurodegeneration.

cell biology↗

bioRxiv2026

Ca2+-activated CKL3 phosphorylates nucleoporin 58 to reprogram nuclear transport and execute effector-triggered immunity

Recognition of pathogen effectors by nucleotide-binding leucine-rich repeat receptors (NLRs) activates effector-triggered immunity (ETI) in plants through resistosome formation, which generates a sustained cytosolic Ca2+ influx and ultimately leads to programmed cell death (PCD) at infection sites and resistance. However, the mechanisms linking Ca2+ influx to ETI execution remains a major knowledge gap. Using TurboID proximity labeling with the central transport channel nucleoporin 58 (Nup58) as a probe, we show that, instead of deregulation, ETI induction restricts general nuclear trafficking while selectively enhancing nuclear import of defense-related proteins. This switch is driven by elevated cytosolic Ca2+, which binds to the conserved Asp-149 in CASEIN KINASE 1-LIKE 3 (CKL3), promoting its interaction with and phosphorylation of Nup58 at Ser-149, thereby altering nuclear pore selectivity. This study identifies CKL3 and Nup58 as key regulators of ETI by establishing a mechanistic link from resistosome-mediated Ca2+ influx to nuclear transport reprogramming and immune execution.

plant biology↗

bioRxiv2026

A Neuroimmune Feedforward Circuit Linking REM Sleep with Stress-Related Behavioral Susceptibility

Rapid eye movement (REM) sleep is strongly associated with stress susceptibility, yet the underlying neuroimmune mechanisms remain unclear, limiting therapeutic targeting. Here, we identify a pathway by which chronic stress increases splenic nerve activity, promoting recruitment of circulating monocytes to the brain through the choroid plexus. In the external globus pallidus (GPe), recruited monocytes drive regionally restricted microglial remodeling toward a pro-inflammatory state. These microglia, in turn, potentiate the sustained excitability of parvalbumin-positive (PV) neurons via IL6-gp130 signaling. Functionally, activity of GPe PV neurons during REM sleep, but not wakefulness, bidirectionally regulates anxiety-like and defensive behaviors, establishing REM sleep as a critical state through which this neuroimmune circuit governs behavioral susceptibility. Together, these findings establish a neuroimmune feedforward mechanism linking peripheral immune activation to neuronal dysregulation underlying behavioral abnormalities, and position REM sleep as a predictive and actionable physiological entry point for mitigating stress-related emotional dysregulation.

neuroscience↗

bioRxiv2026

Widespread use of invalid statistical tests in biomedical machine learning

Cross-validation is routinely used to compare performance in biomedical artificial intelligence. Standard tests ignore correlation across cross-validation folds, inflating false-positive rates. In a PRISMA-guided meta-analysis of 184 studies (impact factor [≥] 15) across 30 biomedical fields, 97% use invalid tests. Among studies with abstract-level claims supported by invalid tests, 59% rely on a spurious comparison: one that loses significance after correcting for this correlation. On average, regaining significance requires a 43% larger effect. Extending these findings to the broader literature, we estimate that spurious comparisons occur in nearly two in three studies and support abstract-level claims in nearly one in three studies. Simulations confirm false-positive rates paradoxically approach 100% when cross-validation is repeated to improve stability. We introduce SHARP, a redesign of cross-validation, which best balances false-positive control and power among 13 benchmarked tests. These results reveal widespread fragility in biomedical artificial intelligence and offer a practical route to valid comparisons.

bioinformatics↗

bioRxiv2026

HLA-G engineering reprograms CAR-T cells with an immune privilege

Personalized T cell therapy empowered by chimeric antigen receptor (CAR) that recognizes specific tumor antigen has cured numerous blood cancer patients since its initial approval in 2017. However, its access to a broader population has been limited by the unavailability of an off-the-shelf product derived from an allogeneic donor that can evade immune rejection, which is mediated by polymorphic class I and class II human leukocyte antigens (HLAs). Since class II HLAs are only expressed in specialized antigen-presenting cells but not T cells, it might suffice to evade T cells by deleting the common class I HLA light chain Beta-2 Microglobulin (B2M) (1). However, B2M-deficient cells can trigger a "missing-self" response to activate natural killer (NK) cells (2), a second function that was evolved to compensate loss of T cell response. Inserting a less polymorphic class I HLA gene encoding a known NK inhibitory ligand, namely HLA-E or HLA-G (3), into the B2M locus so that the endogenous B2M expression is disrupted could theoretically allow evasion of both T and NK cells. Despite being a seemingly better candidate in that HLA-G is uniquely expressed in immune-privileged sites such as the placenta with a believed function in protecting the fetus from immune rejection by the pregnant mother, whereas ubiquitously-expressing HLA-E is known to bind both inhibitory and activating NK receptors (4, 5), only HLA-E engineering has been attempted yet without convincing success in vivo (6, 7). Here, we generate an off-the-shelf CAR-T product with B2M replaced by a gene fusion encoding an HLA-G single-chain trimer under minimally impacted B2M epigenetic landscape, and observe its immune evasion property and a tumor-inhibitory function that is equivalent to its autologous control using a humanized mouse model for the first time with T and NK cells reconstituted from a donor with a distant HLA haplotype. HLA-G engineering may thus reprogram T cells into an immune-privileged state that can be utilized for all cell-based therapies.

immunology↗

bioRxiv2026

Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8+CD 103+ tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/721223v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@34b2f4org.highwire.dtl.DTLVardef@1d0bb89org.highwire.dtl.DTLVardef@c8277borg.highwire.dtl.DTLVardef@9825ac_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic Abstract:C_FLOATNO Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis C_FIG

immunology↗

bioRxiv2026

EA-PheWAS: Integrating Phenotype Embeddings with PheWAS for Enhanced Gene-Phenotype Discovery

Phenome-wide association studies (PheWAS) enable systematic exploration of relationships between genetic variants and clinical phenotypes derived from electronic health records (EHRs). Conventional regression-based PheWAS treats phenotypes separately and relies on binary phenotype representations, which limits statistical power for rare variants and rare phenotypes and reduces the ability to detect associations with phenotypes that are distributed across clinical codes. To address this limitation, we first developed EmbedPheScan, a phenotype embedding-based prioritization framework that summarizes the phenotypic profiles of rare loss-of-function variant carriers in a continuous embedding space. We then proposed EA-PheWAS by combining these embedding-derived signals with conventional regression-based PheWAS results using the aggregated Cauchy association test. Using the UK Biobank whole-exome sequencing and EHR data, we show that the proposed methods maintain appropriate false-positive control. We then performed genome-wide phenome scans across all genes and across biologically defined gene classes to evaluate EA-PheWAS relative to conventional PheWAS and EmbedPheScan, consistently finding that EA-PheWAS outperformed the other two methods. We illustrate the utility of EA-PheWAS focusing on four genes representing distinct scenarios, including strong-effect disease genes (PKD1, PKD2), genes with large numbers of rare LoF carriers (NF1), and genes with extremely sparse carrier counts (FBN1).

genetics↗