Biology subjects

Jin, L.

Publications and source records attributed to Jin, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

GCBM-DCT-HV-Bio-NL-Grow-CHG-CSM-RHEC: A Unified Geometric, Biological, Causal, and Regenerative Framework for Mechanism-Aware Tissue and Connectome Modeling

Modern biological prediction problems increasingly require models that go beyond Euclidean feature regression and local graph smoothing. Tissue, cellular, and connectome systems are nonlinear, geometry-dependent, intervention-sensitive, history-dependent, and subject to regenerative or homeostatic constraints. We propose GCBM-DCT-HV-Bio-NL-Grow-CHG-CSM-RHEC, a unified model for mechanism-aware biological prediction. The model integrates geometric connectome dynamics, differentiable charted tissue geometry, Hamiltonian latent transport, nonlinear biological kinetics, nested latent memory, continual growth without overwriting, causal hypergraph structure, causal structure modeling, and regenerative homeostatic error correction. Unlike Euclidean baselines, which treat observations as flat vectors, and local graph baselines, which use neighborhood smoothing without mechanistic structure, the proposed model represents biological states (Trapnell 2015) as coupled geometric, dynamical, causal, and regenerative objects. We evaluate the model on four synthetic toy studies, Toy A-D, designed to reflect increasing biological complexity: local Euclidean structure, nonlinear mechano-chemical interaction, causal intervention response, and out-of-distribution regenerative shift. Compared with Euclidean and local graph baselines, the full model achieves the lowest mean squared error across all four toy studies. Relative to the Euclidean baseline, the full model reduces MSE by approximately 63.0%, 89.1%, 89.0%, and 90.9% on Toy A, Toy B, Toy C, and Toy D, respectively. These results support the value of integrating geometry, mechanism, causal structure, adaptive growth, and regenerative correction into a single predictive architecture (Figure 1). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/734320v1_fig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@9e9eorg.highwire.dtl.DTLVardef@add398org.highwire.dtl.DTLVardef@1eb1f1org.highwire.dtl.DTLVardef@1346720_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO GCBM-DCT-HV-Bio-NL-Grow-CHG-CSM-RHEC, a unified model for mechanism-aware biological prediction. C_FIG

bioinformatics↗

bioRxiv2026

Systematic Quantitative Proteomics Defines Age, Sex, and Region-Dependent Remodeling of Lung Extracellular Matrix

The lung extracellular matrix (ECM) governs tissue architecture, mechanics, and function, yet how it remodels with age across sex and anatomical regions remains poorly understood. Here, we performed a systematic multi-factor proteomic analysis of rat lungs to define age-, sex-, and region-dependent remodeling across the tissue landscape. Age emerged as the dominant source of variation, with a conserved aging signature modified by region- and sex-specific effects. Young lungs showed coordinated ECM assembly, balanced proteolysis, and active biosynthetic programs consistent with structural adaptability and mechanical resilience. In contrast, aged lungs exhibited accumulation of mature collagen crosslinks and a more stabilized matrix architecture, indicating progressive matrix maturation and reduced structural plasticity. These changes were accompanied by proteomic signatures of metabolic stress and immune activation, suggesting coordinated remodeling across ECM, metabolic, and immune pathways during lung aging. Aging effects varied across anatomical regions and were more pronounced in females, highlighting context-dependent trajectories within the broader aging program. Age also partially reshaped spatial proteomic heterogeneity across lung compartments. Together, these findings identify matrix stabilization as a central feature of lung aging that links structural remodeling to metabolic-inflammatory imbalance and increased pulmonary vulnerability.

biochemistry↗

bioRxiv2026

Ferroptosis is executed through caspase-5 cleavage of gasdermin E in ovarian cancer cells

Ferroptosis, an intracellular iron-catalyzed form of programmed cell death (PCD) driven by lipid reactive oxygen species induced membrane damage, is mechanistically uncharacterized in its execution process. Here, we investigated ferroptosis execution in mesenchymal-like ovarian cancer cells treated with ferroptosis inducers ML162 and erastin. We showed that YVAD (a pyroptosis-associated inflammatory caspase inhibitor) and disulfiram (preventing gasdermin pore formation on plasma membrane) deterred ferroptotic cell death. Moreover, we also observed LDH release and IL-1{beta} secretion from ferroptotic cells, suggesting that ferroptosis involves a pore-forming process. Intriguingly, ferroptosis is independent of the canonical inflammasome pathway because caspase-1 is dispensable and not activated upon ferroptosis induction. In contrast, we found that caspase-5 was activated while caspase-4 was not during ferroptosis. In addition, depletion of caspase-5 rendered cells not responding to ferroptosis inducers. Also intriguingly, GSDMD, the well-established caspase-5 substrate, was not involved in ferroptosis. We instead detected GSDME cleavage upon ferroptosis induction and knockdown of GSDME reduced cell death induced by ferroptosis inducers. As caspase-5 activity was necessary for ferroptosis and caspase-5 directly cleaved GSDME, we conclude that the axis of caspase-5/GSDME executes ferroptosis in ovarian cancer cells.

cell biology↗

bioRxiv2026

Haplotype-resolved Genome Assemblies of Hybrid Wheatgrass and Bluebunch Wheatgrass Reveal the Stepwise Polyploid Origin and Biased Subgenome Dominance

Concerns over climate change have intensified the demand for stress resistant crops like hybrid wheatgrass (HWG; Elymus hoffmannii, StStStStHH), a perennial forage species known for its exceptional salt and drought tolerance. However, hexaploidy and high heterozygosity have complicated efforts to resolve its genomic structure and evolutionary history. Here, we present high-quality, haplotype-resolved, chromosome-level genome assemblies for HWG (CDC Saltking) and its putative progenitor, bluebunch wheatgrass (Pseudoroegneria spicata, StSt). By integrating PacBio HiFi and ultra-long Oxford Nanopore sequencing with Hi-C scaffolding, we assembled the 10.7 Gb HWG genome into 21 pseudochromosomes per haplotype. Our phylogenomic analysis redefines the origin of the H subgenome, positioning it as an intermediate between Old-World Hordeum marinum (sea barley) and Hordeum brevisubulatum. Notably, we identified significant chromosomal rearrangements, including a unique duplication on St chromosome 4. Transcriptome analysis across multiple tissues revealed a pronounced expression dominance of the H subgenome. This dominance was not associated with reduced LTR density, suggesting that selective pressures for rapid adaptation of the latest subgenome entrant may drive its dominance. Finally, using the f-branch statistic, population genomic analysis of 189 accessions representing eight Elymus and Pseudoroegneria species revealed extensive reticulate evolutionary relationships and identified P. spicata as a major, asymmetric genetic donor within the wheatgrass complex. These resources provide a foundational framework for future genomic research and genetic improvement in grasses and for the introgression of stress-tolerance traits into cereal crops such as wheat. Key MessagesO_LIDevelopment of world-first high-quality chromosomal-level haplotype-resolved genome assemblies of hexaploid HWG and diploid progenitor, Pseudoroegneria spicata, enabled the identification of the subgenome origins. C_LIO_LIThis study resolved the evolutionary placement of the St genome and clarified the history of polyploidization and hybridization in HWG. C_LIO_LIHomeolog expression bias in the H subgenome likely reflects selective pressure favoring greater gene retention and upregulation of functionally important genes, thereby enhancing hybrid fitness. C_LIO_LIPopulation structure analysis distinctly differentiates P. spicata, E. repens, E. hoffmannii from other European Pseudoroegneria species. C_LIO_LIThe findings reveal the complex patterns of interspecific gene flow and population dynamics within the Elymus and Pseudoroegneria species. C_LI

genomics↗

bioRxiv2026

Dynein-dependent positioning of multiple organelles regulates adaptive gene expression during oxidative stress

Cells respond to environmental insults through well-characterized changes to their transcriptome and proteome. The contribution that reorganization of intracellular architecture makes to the adaptive stress response is much less understood. Here, we reveal a conserved spatial response to oxidative stress in which the microtubule motor dynein enhances perinuclear clustering of multiple membrane-bound organelles. These events are triggered by reactive oxygen species and protein kinase C and occur without increased association of dynein with its activator dynactin, pointing to a non-canonical mechanism for stimulating retrograde transport. Using a chemically-inducible system for dispersing individual organelles, we show that perinuclear localization of multiple compartments potentiates oxidative stress-induced gene expression, with distinct genes depending on inputs from either combinations of organelles or individual compartments. Together, these findings implicate positioning of multiple membrane-bound compartments in gene expression regulation and identify coordinated organelle trafficking by dynein as an additional regulatory layer in the cellular stress response.

cell biology↗

bioRxiv2026

A vagal gut-brain axis for feeding induced gastric secretion

Feeding begins with food-seeking and ends with nutrient absorption and waste elimination. Although meal-related sensory cues are known to shape feeding behavior, how they engage neural circuits to control digestion remains unclear. We dissected vagal gut-brain-gut pathways that mediate meal-induced gastric secretion. Vagal afferent neurons innervating the stomach were necessary and sufficient for secretion. Among those, Glp1r and Sst neurons robustly drove acid, pepsin, and gastrin secretion, whereas Oxtr and Vip neurons had little effect. Piezo2 was expressed in Glp1r mechanosensory afferents, and conditional deletion of Piezo channels attenuated distension-evoked secretion. On the efferent limb, genetically defined vagal motor neuron subsets differentially recruited secretory outputs: Cck neurons broadly increased acid, pepsin, and gastrin, whereas Grp neurons preferentially drove acid secretion. Finally, enteric circuit dissection revealed modular output control: Calb2 enteric neurons potently drove secretion with minimal motility effects, Grp enteric neurons coupled secretion to motility, and Cysltr2 enteric neurons selectively modulated acid output. Together, these results define a cell-type resolved vagal-enteric architecture for gastric control and show that secretory and motor programs can be segregated across dedicated enteric neuron subtypes.

neuroscience↗

bioRxiv2026

Refinement of Nucleus Accumbens Neuronal Dynamics During Cocaine Self-Administration Training

Drug addiction is an acquired motivational-behavioral state that begins with drug taking, which is comprised of a series of phases, including initial acquisition, stabilization, habituation, and maintenance. In rodent models of cocaine self-administration, the forebrain region nucleus accumbens (NAc) has been critically implicated in the acquisition-maintenance process of drug taking and seeking behaviors. However, it remains unknown how NAc neurons shift their activity patterns in response to these phasic transitions during cocaine taking. To examine this, we used GCaMP6m-based in vivo Ca2+ imaging to monitor activities of principal medium spiny neurons (MSNs) in the NAc across eleven days of cocaine self-administration. Behaviorally, mice exhibited progressive stabilization of operant responding and locomotion across 11 days of cocaine self-administration. During the early training days, we detected a portion of NAc neurons--a potential neuronal ensemble--that exhibited increased activities temporally contingent to the lever-press for cocaine. The number of NAc neurons exhibiting contingent activity increased progressively over the first three training days and then decreased gradually during the later training days, exhibiting expansion-refinement dynamics that may correspond to the acquisition and subsequent stabilization/maintenance of cocaine self-administration. Using a neuron-tracking technique, we found that the lever-press-contingent NAc ensemble exhibited substantial compositional dynamics, with neurons dropping into and out across training days. These activity features of lever-press-contingent neurons may represent key circuit dynamics of the NAc that transition the acquisition toward the maintenance of cocaine-taking behavior.

neuroscience↗

bioRxiv2026

Engineering an in vitro model of demyelinated spinal cord tissue

Demyelinating diseases are a group of complex neurodegenerative disorders characterized by damage to the myelin, the protective sheath that insulates and supports efficient nerve signal conduction. Such a loss of myelin causes the formation of lesions not only in the brain but also often in the spinal cord (SC). Despite the high prevalence of SC lesions among patients, existing models mostly focus on those in the brain, inadequately capture the unique anatomical and physiological features of SC pathology. In this study, we developed a robust, reproducible in vitro model of SC demyelination by combining microwell technology and piezoelectric scaffolds to engineer human neural stem cell (hNSC)-derived nerve tissues featuring aligned, myelinated, extended axons up to 2000 {micro}m in length. We utilized distinct chemical treatments to induce demyelination with or without axonal degeneration: a cuprizone cocktail, a copper chelator combined with inflammatory cytokines, and lysophosphatidylcholine (LPC). Electrophysiological assessments validated the physiological relevance of our model, demonstrating impaired signal transmission and neural connectivity akin to in vivo demyelination pathology. Our versatile platform thus provides a valuable tool for elucidating SC demyelination pathophysiology and exploring potential therapeutic interventions.

bioengineering↗

bioRxiv2026

Metabolic Repression of Autophagy Drives Inflammation, Pain, and Malodor in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a debilitating and underdiagnosed inflammatory skin disease with limited therapeutic options due to an incomplete understanding of its molecular and immunopathogenic basis. Using an integrated multi-omics approach, we delineate convergent pathways linking dysregulated autophagy, malodour, and pain in HS. Lesional tissues exhibited sustained autophagy repression, marked by increased expression and activation of mTOR and ZKSCAN3, reduced levels of autolysosome-promoting metabolites {beta}-hydroxybutyrate and nicotinamide riboside, and accumulation of fructose-1,6-bisphosphate, a negative regulator of AMPK. Transcriptomic analyses identified cadaverine derivatives as key metabolic drivers of keratinocyte reprogramming, inducing gene networks associated with hyperproliferation, inflammation, fibrosis, nociception, and the characteristic carrion-like odour of HS. Concordantly, ATAC-seq revealed increased chromatin accessibility at loci encoding TRP channels and histamine receptors, consistent with heightened nociceptive signalling. Multi-layered proteomics, phospho-proteomics, kinomics, and spatial proteomics analyses, validated by high-resolution confocal imaging, demonstrated elevated mTOR (Ser2448), ZKSCAN3, and P62, alongside reduced LAMP1, across keratinocytes and immune cell populations including CD4 T cells, CD56 NK cells, and CD68 macrophages. Inhibition of mTOR normalized transcriptional programs and cytokine production linked to NLRP3 inflammasome, restoring tissue homeostasis. Collectively, these findings identify a metabolically reinforced mTOR-ZKSCAN3 axis in autophagy dysregulation and cadaverine-driven epithelial reprogramming as central mechanisms sustaining inflammation, pain, and fibrosis in HS. HighlightsO_LIWe identified BCAAs, BHB, NR, and FBP as key metabolites linked to mTOR activation and autophagy dysregulation in HS. C_LIO_LIPolyamines like cadaverine and putrescine, their acetylated derivatives, LPCs, and endocannabinoid dysregulation likely drive malodor and pain in HS. C_LIO_LICadaverine treatment of Ker-CT cells induces HS-associated gene signatures of inflammation, fibrosis, and pain. C_LIO_LIIdentification of an HS macrophage subpopulation expressing ZKSCAN3 with activated mTOR and impaired autophagy. C_LI

immunology↗

bioRxiv2025

Isoflavones impair response to anti-PD1 therapy in murine breast cancer models, irrespective of dietary fiber and fecal short chain fatty acid levels

BackgroundFermentable dietary fibers, also called microbiota-accessible carbohydrates (MAC), and the consequent increase in fecal short-chain fatty acids (SCFAs) are linked to improved responsiveness to immune checkpoint blockade (ICB) therapy in human and mouse studies. However, experimental diets high in MAC also often contain estrogenic isoflavones, which may counter fibers beneficial effects by causing immunosuppression. MethodsWe studied the effects of feeding female C57BL/6Tac mice low-MAC (AIN93G), low-MAC supplemented with isoflavone genistein, high-MAC (5V5M) or high-MAC isoflavone (high-MACi; 5058D) diet on their gut microbiome and response to anti-PD1 therapy against E0771 allografted triple negative breast cancer (TNBC) and 7,12-dimethylbenz[a]anthracene (DMBA)-initiated estrogen receptor positive (ER+) mammary tumors. We also determined whether blocking ER with tamoxifen (TAM) impacted responsiveness to anti-PD1 therapy in mice fed different diets. The effect of diet and treatments on immune cell signaling pathways was investigated using NanoString PanCancer Immune Profiling Panel. ResultsHigh-MAC and high-MACi diets increased fecal microbial alpha-diversity and the abundances of SCFA producing families Lachnospiraceae, and Oscillospiraceae as well as fecal SCFA levels, compared with low-MAC diet. E0771 tumors responded to anti-PD1 in mice fed high-MAC, while mice fed high-MACi did not respond. Low-MAC fed mice with single E0771 allograft also responded to anti-PD1, but genistein supplementation eliminated responsiveness. E0771 tumors in high-MAC fed mice contained elevated levels of exhausted CD8+ T cells, which were decreased after anti-PD1 therapy. Opposite effects were seen in mice fed high-MACi diet. Mice with DMBA-initiated ER+ mammary tumors did not respond to anti-PD1. TAM converted TNBC and ER+ tumors to become sensitive to anti-PD1 therapy in mice fed high-MACi or low-MAC diets, respectively. Genes in TH17 differentiation pathways were linked to TAM-induced improved anti-PD1 response both in TNBC and ER+ mammary tumors. ConclusionsOur results highlight the role of diet in impacting the effectiveness of ICB therapies. We found that increased SCFA levels alone are not predictive of response to anti-PD1, but if tumor expresses ER or if diet contains ER activating compounds, such as isoflavones, blocking ER+ might convert unresponsive tumors responsive to anti-PD1. Word count: 339 What is already known on this topicDietary fiber is proposed to improve response to checkpoint inhibitor therapy against melanoma, but this has been challenged by a recent preclinical study in which different mouse tumor models were used. None of the studies have been done in breast cancer or preclinical breast cancer models. What this study addsOur study showed, using triple negative breast cancer (TNBC) and estrogen receptor positive (ER+) breast cancer models, that indeed high levels of microbiota accessible carbohydrates (MACs) in diet did not alone determine responsiveness to anti-PD1 therapy, but diet high in plant isoflavones/ hormones impaired anti-PD1 effectiveness, regardless of whether diet contained high fiber levels or not. We also found that the adverse effects of isoflavones were counteracted by tamoxifen, partial estrogen receptor antagonist. How this study might affect research, practice or policyOur findings could indicate that breast cancer patients, both those with TNBC and ER+ disease, should not consume diets high in isoflavones when treated with anti-PD1.

cancer biology↗

bioRxiv2025

Beyond Correlation: An Ultra-Large Physics-Driven Vascularized Tumor Model to Bridge Feature Formation with Underlying Biology

Radiomics provides an appealing, non-invasive approach to probing tumor biology for potential diagnostic and prognostic applications. However, its clinical adoption is limited by challenges in interpretability, which in turn compromise its robustness. To uncover the underlying causation, we developed an ultra-large-scale (ULS) computational model that simulates heterogeneous, vascularized tumor growth under physical constraints to a scale that can be visualized in medical images. Our study revealed the pivotal role of tumor proliferation rate in driving necrosis and tissue heterogeneity and the dominant impact of oxygen consumption rate on vascularization level. Analysis of the resultant tumor Radiomics shows a causal relationship between tumor biophysical parameters and imaging features. Specifically, differences in proliferation and oxygen consumption rates result in distinct changes in radiomic image features, identifying suitable imaging modalities and quantitative imaging metrics for studying these biophysical parameters. This work thus reverse-engineers the building blocks of Radiomics as a means to understand their respective biological underpinnings.

bioinformatics↗

bioRxiv2025

De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis

Fasting blood uridine is increased in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis to the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and diet-induced obesity, while suppression of hepatic pyrimidine synthesis promotes obesity and insulin resistance. The metabolic sequalae of hepatic pyrimidine synthesis suppression, however, is not associated with altered plasma uridine concentration. Instead, it is associated with an increased hepatic glucose production and a decreased hepatic insulin clearance, two key functions of hepatocytes in regulating systemic energy homeostasis. We found that enhanced gluconeogenesis is the primary reason for increased hepatic glucose production. Moreover, uridine, which was maintained stable in the circulation by adipose tissue and the liver, preferentially shut down pyrimidine synthesis in hepatocytes but not adipocytes at blood concentrations that occur with fasting. Remarkably, uridine, at fasting levels, increases gluconeogenesis further in hepatocytes when de novo pyrimidine synthesis is suppressed, indicating a synergistical action of uridine and its biosynthesis pathway in promoting hepatic glucose production, a mechanism highly relevant to the pathophysiology of insulin resistance in obesity. Theologically, maintenance of blood uridine within the narrow range protects mammals from high-rate spontaneous tumorigenesis. Since obesity promotes an increase in blood uridine from adipocytes, suppressing uridine synthesis in hepatocytes becomes a critical response to lower spontaneous tumorigenesis. Pyrimidine synthesis suppression in hepatocytes, however, promotes gluconeogenesis and ultimately triggers obesity and T2D. These findings suggest a new paradigm for the etiology of metabolic deterioration in diet-induced obesity, in which perturbations in uridine promotes obesity and T2D.

pathology↗

bioRxiv2025

GNAT: An Interactive Web Tool for Gene Neighbourhood Analysis

Given the sequence of a protein, the Gene Neighbourhood Analysis Tool (GNAT) identifies homologues within microbial (bacterial, archaeal, or fungal) or viral databases, aligns and clusters their genomic neighbourhoods (GNs) by similarity, reports the taxonomic distribution of matched genomes, and generates interactive, publication-quality visualizations with customizable annotations, colours, and display options, along with categorical and quantitative summary analytics. GNATs intuitive interface enables a broad community of researchers to generate biological insights from GNs without requiring computational expertise and serves as a comprehensive and versatile platform for easily comparing GNs across the domains of life. GNAT is accessible at https://gnat.usask.ca.

bioinformatics↗

bioRxiv2025

BCKDK, a novel hypoxia-responsive kinase that exacerbates cerebral ischemia injury

Alterations of circulating amino acid profile have been observed in patients with ischemic stroke. However, whether ischemia disrupts amino acid metabolism in the brain tissue and subsequently potentiates cellular stress and cerebral injury have never been explored. Employing a metabolomics approach combined with metabolic flux analysis, impaired catabolism and significant enrichment of branched-chain amino acids (BCAAs) were identified in mouse primary neuron cells upon oxygen-glucose deprivation. Consistently, BCAA catabolism was also damaged in the brain of mouse with acute ischemic stroke, accompanied with suppressed activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) and upregulation of BCKDH kinase (BCKDK). Furthermore, restoration of BCAA catabolism by suppressing BCKDK via pharmacological inhibitor or silencing RNA dramatically alleviated cerebral ischemia injury in mice. Mechanistically, ischemia induces the expression of BCKDK via hypoxia-inducible factor 1-mediated transcriptional activation and inhibits BCAA conversion into substrates for tricarboxylic acid cycle, contributing to potentiated energy deficiency, glutamate excitotoxicity, and neuronal injury. Collectively, this study identified BCKDK as a novel hypoxia-responsive factor and a promising therapeutic target for cerebral ischemia injury.

molecular biology↗

bioRxiv2025

Multi-omics reveals lipid metabolism, mitochondrial and extracellular matrix dysregulation of diabetic cardiomyopathy in the human heart

Diabetic cardiomyopathy (DbCM) is a condition characterized by myocardial dysfunction in diabetes. Although the clinical recognition of DbCM is increasing, its underlying molecular mechanisms remain poorly understood. We aimed to conduct a comprehensive multi-omics analysis of heart tissue from cardiomyopathy patients (both with and without diabetes),alongside tissue from healthy donors, by integrating transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic data. Differential analyses revealed a significant metabolic pattern in patients with DbCM, characterized by increasing utilization of triglyceride-derived fatty acids. Correlation analyses highlighted impaired BNIP3L-mediated mitophagy as a potential contributor to the disruption of fatty acid metabolism and mitochondrial dysfunction in DbCM. Protein interaction and fibrotic trichrome analyses showed that patients with DbCM had impaired cardiac matrix repair compared to patients with cardiomyopathy without diabetes. These findings provide a system-level understanding of DbCM and reveal molecular signatures driving its progression, offering insights for targeted therapeutic strategies against diabetic heart disease.

bioinformatics↗

bioRxiv2025

The structure of Egalitarian in complex with the K10 mRNA localization signal reveals a modular binding surface required for function

Asymmetric localization of mRNAs is a prevalent mechanism for spatial control of protein function and typically involves active transport by cytoskeletal motors. The mechanisms of recognition of localizing mRNAs by motor complexes are poorly understood. Egalitarian is an adaptor protein that binds localization signals in specific RNAs in Drosophila and recruits them to the dynein-dynactin complex for microtubule-based transport. We determined the crystal structure of Egalitarian in complex with the localization signal of the K10 mRNA. Three structural units of Egalitarian, a 3'-5'exonuclease domain, a linker and a C-terminal domain form shape-specific, base-directed and backbone interactions with the RNA. Based on the structure we identified conserved residues recognizing RNA in vitro. Genome-edited flies with mutations in these residues have deficits in Egalitarian function that are congruent with changes in in vitro RNA binding affinities. Our work demonstrates how a minimal RNA localization signal is recognized by an RNA localization factor.

biochemistry↗

bioRxiv2025

Helminth infection favors reprogramming and proliferation of lung neutrophils

Neutrophils are a granulocytic population of myeloid cells that have critical effector functions during infectious disease but are generally thought to be short-lived and nonproliferative with markedly limited activation states. In these studies, we directly compared lung neutrophil activation following infection with different groups of pathogens including bacteria, fungi, and helminths. Our results demonstrate considerable heterogeneity depending on the type of infectious agent. In contrast to bacterial and fungal infection, after helminth infection neutrophils expressed markers associated with characteristic type 2 responses and unexpectedly upregulated genes associated with cell cycling and protein synthesis. Further studies showed reduced neutrophil cell death following helminth infection and increased proliferation, which was dependent on IL-4R signaling. This distinct subset of proliferating neutrophils expanded following helminth infection and was released from the endothelial niche to colocalize with invading parasites in the airways. These studies demonstrate a novel long-lived cycling phenotype for neutrophils following helminth infection.

immunology↗

bioRxiv2025

Phase separation of Polycomb-like (PCL) proteins drive PRC2 complex condensates to regulate gene expression

Polycomb group (PcG) proteins function as two major multicomponent protein complexes: Polycomb repressive complex 1 (PRC1) and 2 (PRC2) to repress key developmental genes and maintain epigenetic memory of cell identity during development. Phase-separation has long been implicated in PRC1 mediated gene silencing, but it is still unclear whether PRC2 also utilize a similar mechanism to regulate gene expression. Here we report that Polycomb-like (PCL) proteins, PRC2 accessory factors, can phase-separate in vitro and generate dynamic puncta in vivo. Biochemical and cellular analyses reveal that PCL proteins (hereafter referred to as PCLs) have intramolecular interaction between N- and C-terminal domains, which make PCLs into more compact conformations. The intramolecular interaction not only controls the size of the PCLs phase separation droplets, but also affects the chromatin association of PRC2. Finally, we show that CpG islands, key DNA regulatory elements in mammalian promoters, disrupt the N-C intramolecular interaction of PCLs to expose their middle intrinsically disordered regions (IDRs), which in turn trigger PCLs driven PRC2 condensates formation. Together, this study provides a new perspective on the regulation of PRC2 by PCLs, implicating PCLs read CpG islands to fine-tune their oligomerization to overcome the threshold for PRC2 recruitment to corresponding genomic loci via multivalent interaction with CpG islands chromatin.

biochemistry↗