Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2026

Capabilities, specificity gaps and training-data dependence of AlphaFold3 across diverse application areas

Structure prediction models have moved from single proteins to assemblies that include diverse biomolecules and their modifications. AlphaFold3 (AF3) and related models extended structural modelling via an all-atom framework, opening many new potential applications in structural biology. We evaluate how well the new capabilities of AF3 translate into application tasks in diverse areas: prediction of ubiquitinated protein structures, T-cell receptor (TCR)-epitope recognition, antibody-antigen complexes, protein-RNA and protein-lipid interactions. We find that, while AF3 can perform well in favourable settings, this performance is uneven across applications. In RNA-target predictions, the model confidence fails to separate genuine from decoy interaction partners and in several tasks accuracy depends on the presence of related complexes in the training set. Taken together, our assessment is more cautious than for AF2, whose gains in modelling monomers and complexes were clear and broadly generalisable. AF3s extension to new biomolecule types shows less consistent performance and generalisation. AF3 can be a powerful tool for hypothesis generation and prioritisation, but its predictions and use of confidence metrics will depend strongly on the specific application area and must be interpreted with respect to training-set overlap. We expect that the benchmarks provided here will serve for testing of future developments in the structure prediction field.

bioinformatics↗

bioRxiv2026

Age-Associated Behavioral Alterations in Laboratory-Housed Octodon degus

Octodon degus are long-lived, diurnal, and highly social rodents increasingly used in studies of aging and neurodegeneration. However, behavioral profiles of aged laboratory-housed degus remain incompletely characterized, limiting the interpretation of aging-associated functional and molecular phenotypes in this species. Here, we evaluated age-associated changes in locomotor activity, open-field exploration, social novelty behavior, and manually scored ethological responses in young and old degus maintained under long-term laboratory housing conditions. Automated behavioral tracking was performed during open-field testing and three-chamber social behavior testing. During open-field testing, old degus showed increased locomotor activity compared with young animals, including greater total distance moved, higher mean velocity, increased moving frequency, and longer cumulative movement duration. Old degus also showed increased center-zone duration and reduced thigmotaxis score. Manual ethological scoring revealed increased rearing and fecal boli in old animals during open-field exposure. In the three-chamber social behavior assay, young degus showed higher investigation frequency toward the novel intruder than toward the familiar cagemate, whereas old degus showed a lower social novelty discrimination index compared with young animals. Sex-stratified analyses did not identify significant male-female differences within young or old groups for the major open-field or social novelty metrics examined. Together, these findings indicate that aging in laboratory-housed degus is associated with a mixed behavioral profile involving increased stress-related ethological responses and reduced social novelty preference reminiscent of dementia-like behavioral changes observed in Alzheimers disease. This behavioral framework provides a practical reference for future studies examining behavioral heterogeneity and molecular correlates of brain aging in degus. Lay SummaryOctodon degus are long-lived, highly social rodents that are increasingly used to study aging and age-related neurodegenerative disorders. However, interpreting behavioral changes in aged degus requires a clear understanding of how aging affects activity, exploration, social behavior, and stress-related responses under laboratory housing conditions. In this study, we compared young and old degus using open-field testing, three-chamber social behavior testing, automated video tracking, and manual scoring of selected behaviors. Aged degus did not show a simple reduction in behavioral activity. Instead, they showed increased movement during behavioral testing, increased rearing behavior, greater exploration of the center of the open-field arena, and increased fecal output during open-field exposure. These findings suggest that aged degus show increased exploratory activity together with altered stress-related responses in a novel environment. Aged degus also showed reduced preference for investigating a novel social partner, consistent with a dementia-like cognitive impairment. Together, these results define a behavioral profile of aged laboratory-housed degus and provide a practical reference for future studies using this species to investigate aging, social behavior, and neurodegeneration-related phenotypes.

neuroscience↗

bioRxiv2026

GAMETE maps the genetic architecture of chromatin accessibility in rice pollen at single-nucleus resolution

BackgroundDissecting the genetic basis of cell-type-specific gene regulation during gametogenesis remains a major challenge. Population-level studies mask cellular heterogeneity, while the extreme data sparsity of single-cell profiling has precluded robust genetic mapping. ResultsWe present GAMETE (Genetic Architecture Mapping of Epigenetic Traits at single-nucleus resolution), an integrated framework combining MPS-ATAC-seq, a high-throughput single-nucleus ATAC-seq method, with robust computational approaches for genotype inference and genetic mapping from sparse single-nucleus data. Applying GAMETE to hybrid rice pollen, we simultaneously profiled chromatin accessibility and inferred the genotypes of 4,887 individual haploid nuclei, revealing distinct chromatin landscapes across pollen cell types. This uncovered an unexpected elevation of chromatin accessibility at gypsy retrotransposons in microspores preceding their silencing in sperm cells, exposing a surveillance gap that may contribute to genome expansion. The synchronized profiling enabled us to construct a single-cell recombination map, map segregation distortion loci and trace their developmental origins, and identify 16,113 chromatin accessibility QTLs (caQTLs), 48.6% of which exhibited pronounced cell-type specificity. Analysis of introgression lines supported a cell-type-specific trans-acting caQTL regulating the pollen-essential gene DTM1. ConclusionsThis work establishes GAMETE as a broadly applicable framework for dissecting the genetic architecture of chromatin accessibility during gametogenesis without the need for subsequent generations.

genomics↗

bioRxiv2026

Bone Mechanosensing Dictates Hematopoietic Stem Cell Fate and Immune Homeostasis

The vertebrate water-to-land transition was accompanied by a six-fold increase in gravitational force, followed by the migration of hematopoietic stem cells (HSCs) from kidney or liver to the bone marrow, and the acquisition of enhanced immune functions to cope with novel environmental pressures. Bone senses mechanical loading and provides a microenvironment for HSC development, yet whether bone mechanosensation affects immune cell development and immune homeostasis remains unclear. Here, we unveil bone as a mechanosensory organ that translates mechanical force into hematopoietic instructions. Mechanical loading of bone directs HSCs toward lymphoid lineages in mice and non-human primates, whereas unloading favors myeloid commitment. This process requires osteocyte mechanosensor Piezo1, which induces loading-responsive bone-derived factors such as IL1R2, SERPINC1 and INMT, thereby restraining inflammatory signaling and guiding HSC differentiation. Osteocyte Piezo1 deficiency recapitulates the hematopoietic and immune alterations observed during unloading. Functionally, this pathway enhances acute infection resistance and suppresses immunosenescence in mice and in aged long-tailed macaques. Notably, skeletal mechanoregulation of immune homeostasis is conserved across vertebrate species. Our research defines the mechano-bone-immune axis (mechano-osteoimmunology), offering a novel evolutionary perspective on the interconnected development of the skeletal and immune systems and presenting a promising non-pharmacological target to address immune dysfunction.

immunology↗

bioRxiv2026

Long-Timescale Molecular Dynamics Reveal a Coordination-Biased Conformational Selection Mechanism for Sorcin Activation

Sorcin is a dimeric penta-EF-hand Ca2+-binding protein that regulates intracellular Ca2+ homeostasis through Ca2+-dependent conformational activation and target recognition, and it has also been implicated in multidrug resistance in cancer. Although crystal structures have defined the apo inactive and Ca2+-bound active states of Sorcin, the transition pathways connecting these states and the conformational ensembles populated under each condition remain poorly understood. Here, we used long-timescale all-atom molecular dynamics simulations on Anton 3, totaling [~]90 s, to define the Ca2+-coupled conformational landscape of dimeric human Sorcin at atomic resolution. Starting from the Ca2+-bound structure, we directly observed the transition from the active to the inactive state following Ca2+ removal, demonstrating that loss of Ca2+ coordination is sufficient to drive inactivation on the microsecond timescale. Simulations initiated from the Ca2+-bound crystal structure with retained ions unexpectedly revealed ultrafast Ca2+ dissociation and rebinding at all EF-hand sites, indicating weak intrinsic Ca2+ affinity and highly dynamic ion exchange. In complementary simulations initiated from the apo structure, Sorcin spontaneously sampled active-like conformations even in the absence of stable Ca2+ binding, supporting a conformational selection mechanism in which Ca2+ shifts the population toward pre-existing active states rather than inducing the transition de novo. Across all conditions, we also observed pronounced and persistent structural asymmetry between the two protomers, revealing that the Sorcin homodimer is dynamically heterogeneous despite its symmetric crystal structures. Together, these results support a coordination-biased conformational selection model for Sorcin activation, in which weak and rapidly exchanging Ca2+ binding stabilizes, rather than induces, the active state. This work provides a dynamic framework for understanding Sorcin function as a fast Ca2+ sensor and offers broader mechanistic insight into activation principles of EF-hand Ca2+-binding proteins.

biophysics↗

bioRxiv2026

Toward pharmacologic therapy for glioblastoma: Characterization of the very long-chain acyl-CoA synthetase 3 (ACSVL3) inhibitor Grassofermata

Malignant brain tumors are among the most aggressive and difficult to treat human cancers. Glioblastomas (World Health Organization grade IV gliomas) are particularly lethal and refractory to treatment. Few drugs exist that are even somewhat effective. Our investigation of the physiologic role of fatty acid (FA) activating enzymes (acyl-CoA synthetase; ACS) identified an ACS that was widely expressed in gliomas but not in normal glial cells. Depletion of this enzyme, ACSVL3 (very long-chain ACS3), by knockdown or knockout decreased the malignant behavior of several glioma cell models including U87MG and Mayo-22 cells both in culture and when grown as xenografts. Hypothesizing that ACSVL3 is a potential therapeutic target in glioma, we conducted a search for inhibitors of this enzyme and found that CB5 (grassofermata) was a promising candidate. Treating U87MG glioma cells with CB5 slowed growth in monolayer culture; the growth rate was similar to that seen in cells in which ACSVL3 was either knocked down or knocked out. CB5 inhibited growth in a dose-dependent manner over a narrow range, and concentrations above 10 {micro}M were toxic. Treatment at the lower dose of 3 {micro}M inhibited growth of U87MG cells but was reversible, suggesting that this dose was not toxic. CB5-treated U87MG cells exhibited an altered morphology with a larger size and longer projections. In contrast, normal human fibroblasts treated with 10 {micro}M CB5, a concentration that was toxic to U87MG cells, showed no effect on either growth rate or morphology. Treating U87MG cells with 3 {micro}M CB5 induced differentiation as shown by increased expression of the astrocyte-specific marker glial fibrillary acidic protein (GFAP). In contrast, GFAP levels remained low in ACSVL3 knockdown cells. CB5-treated U87MG cells were less invasive, and thus less malignant, than either untreated cells or ACSVL3 knockout cells when assessed by a scratch wound healing assay. Acute treatment of U87MG cells with 3 {micro}M CB5 decreased the ability of these cells to degrade FA of differing chain lengths from 16-24 carbons by {beta}-oxidation, suggesting that decreased ACS enzyme activity contributes at least in part to the drugs mechanism of action. NOD/SCID mice receiving up to 32 mg/kg/day CB5 by intraperitoneal injection showed no obvious side effects, suggesting that the drug was well-tolerated. Xenografts induced by subcutaneous injection of U87MG cells in the flanks of NOD/SCID mice were allowed to grow for 8 days after which half of the mice were treated with 2 mg/kg/day CB5. After 7 days of treatment, xenograft growth slowed in the treated mice and by 12 days tumor size had begun to decrease, suggesting therapeutic efficacy. When a similar study was done using xenografts induced by subcutaneous injection of Mayo-22 cells, which are maintained as subcutaneous tumors in mice rather than in cell culture, the effect of CB5 on tumor growth or weight at sacrifice was not statistically significant. The results of these studies suggest that CB5 may have therapeutic value in malignant glioma. Additional studies using other glioma models and other drugs chemically related to CB5 seem warranted.

cancer biology↗

bioRxiv2026

A PLK1-Directed Mitotic Genome Maintenance Network Promotes DNA Synthesis in Mitosis

Polo-like kinase 1 (PLK1) is a master regulator of mitosis and is known to dictate DNA repair pathway choice at this stage of the cell cycle. However, its roles in controlling mitotic DNA damage responses remain incompletely characterised. Here, we used acute PLK1 inhibition as a substrate-trapping strategy to stabilise PLK1-target interactions in mitotic cells and identify PLK1-associated DNA repair factors. Proteomic analysis of endogenous HA-tagged PLK1 complexes revealed interactions with multiple genome stability proteins, including SLX4, RAD52, FANCM, and REV1. We demonstrate that PLK1 binds SLX4 and RAD52 via canonical CDK1-dependent phospho-docking motifs centred on SLX4 Ser1453 and RAD52 Thr300. Mutation of these residues abolished PLK1 binding and, at least for RAD52, prevented PLK1-dependent phosphorylation of mitotic targets. Functional analyses showed that PLK1 docking to SLX4 is dispensable for interstrand crosslink repair but essential for mitotic DNA synthesis (MiDAS), defining a separation-of-function allele. Likewise, disruption of PLK1 docking to RAD52 impaired MiDAS. Together, these findings identify PLK1 as a key coordinator of mitotic genome maintenance pathways required for MiDAS.

cell biology↗

bioRxiv2026

Water as a thermal contrast agent for artificial-intelligence-enhanced in vivo mid-infrared thermography

In vivo infrared thermography is limited by the inherently poor spatial resolution at long wavelengths, low contrast, and the lack of biocompatible contrast agents. Here, we present 3-5 m mid-wave infrared (MWIR) thermography enhanced by an artificial intelligence (AI) network and cold phosphate-buffered saline (PBS) as a thermal contrast agent for noninvasive in vivo imaging with high contrast and resolution. MWIR imaging enabled high thermal sensitivity with microscale spatial resolution, strong relative thermal contrast, and facilitated visualization of the subcutaneous vasculature in the human arm, hand, ankle, the femoral artery and vein in rats, and the femoral vessels in mice, with image contrast further enhanced by AI networks. In a 4T1 tumor-bearing mouse model, AI-enhanced MWIR resolved early-stage tumors of [~]2.3 mm and metastases as small as [~]1.7 mm. Using cold PBS as a MWIR thermal contrast agent, we achieved precise tumor boundary visualization and real-time imaging-guided tumor resection. AI-enhanced MWIR offers a promising solution for early diagnosis and improved surgical precision.

bioengineering↗

bioRxiv2026

Short-term methionine starvation induces de novo diurnal oscillations of hepatic m6A RNA methylation

Dietary methionine restriction has been shown to improve metabolic health and treat multiple diseases. Methionine metabolism regulates transmethylation reactions, including N6-methyladenosine (m6A) RNA methylation, by modulating the availability of S-adenosyl methionine (SAM). Both m6A RNA methylation and methionine metabolism are involved in the regulation of the circadian clock. However, it remains unclear whether dietary methionine influences circadian rhythms through the regulation of m6A RNA modification. In this study, we investigated the effects of short-term methionine deprivation on the diurnal oscillations of m6A RNA methylation in the mouse liver. We found that a methionine-deficient (MD) diet reprogrammed the cyclic expression patterns of m6A writers, erasers, and readers. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that the MD diet induced de novo diurnal m6A oscillations in genes associated with RNA processing, protein translation, protein ubiquitination, and mTORC1 signaling pathways. RNA-seq and quantitative proteomics analyses demonstrated that MD-induced changes in m6A RNA levels were linked to alterations in mRNA and protein abundance. We observed that dynamic m6A RNA methylation of the transcripts encoding two key enzymes, MAT2A and CBS, helps maintain methionine homeostasis in response to methionine starvation. These findings identify m6A RNA methylation as a key mechanism linking methionine metabolism to circadian regulation.

molecular biology↗

bioRxiv2026

First community challenge for automated virus taxonomy

The rapid rate of virus discovery renders manual curation by taxonomy experts increasingly impractical, creating a need for reliable software that can reproducibly assign viral contigs to taxa at all fifteen ranks of the virus taxonomy. We led an open community challenge for the computational taxonomic classification of viruses and assembled a dataset of virus sequences combining expert-curated and metagenomic sequences. Seventeen teams contributed a total of thirty-four automated, fully reproducible classification pipelines. Most tools correctly assigned viruses belonging to established species, genera, or families, but viruses that are unclassified at those lower ranks remain challenging. This study provides datasets, open-source software, novel approaches, and recommendations to benchmark computational taxonomic classification of viruses, and support organizing the many viruses discovered in big omics data.

microbiology↗

bioRxiv2026

Cohesin residence time gates 3D genome response to histone hyperacetylation

Cohesin-mediated loop extrusion and chromatin state-dependent compartmentalization are major drivers of three-dimensional (3D) genome organization. Although epigenomic perturbations are widely assumed to reshape chromatin architecture, the mechanisms that determine how changes in chromatin state are translated into structural reorganization remain poorly understood. Here, we identify cohesin residence time as a key regulator of the genomes architectural response to histone hyperacetylation induced by histone deacetylase inhibition (HDACi). Acute depletion of RAD21 or CTCF weakens chromatin loops but preserves HDACi-induced changes in compartmentalization, contact-scaling behavior, and loop density. In contrast, perturbation of cohesin loading or release produces opposing effects: NIPBL depletion sensitizes and amplifies architectural responses to HDACi, whereas WAPL loss renders the genome largely refractory to HDACi-induced remodeling, suppressing changes in compartments and loop density while stabilizing CTCF-anchored loops. These distinct architectural outcomes occur despite comparable levels of HDACi-induced histone hyperacetylation across genotypes, indicating that differential epigenomic input is not responsible for the observed effects. Together, our findings demonstrate that dynamic cohesin turnover, rather than cohesin chromatin association alone, governs whether epigenomic perturbations are converted into higher-order genome reorganization. These results establish cohesin residence time as a molecular gate linking chromatin state to 3D genome architecture and reveal a previously unrecognized principle underlying chromatin architecture plasticity.

genomics↗

bioRxiv2026

P-DOpE probes reveal local amplification of phasic noradrenergic release in the hippocampus

Fiber photometry (FP) has become a tool of choice for in vivo monitoring of genetically encoded biosensors. The ability to record and optogenetically manipulate circuits through the same fiber stub is powerful, but limited, as biosensors typically do not sample membrane voltage, leaving the experimenter blind to the direct effects of opsin photoactivation. Here we developed the Photometry Device with Optogenetics and Electrophysiology (P-DOpE) probe, fabricated via a new convergence taper-break (CTB) method that integrates industry-standard silica optical waveguides with low-impedance metal electrodes that can be arranged in experimenter-defined configurations. We demonstrate that chronically implanted P-DOpE probes provide months-long recordings of local field potential, single unit recording, and fiber photometry, with parallel optogenetic circuit perturbation. Conducting fiber photometry with same-site optogenetic stimulation, we identified a robust fluorescence signal that scaled with network activity and survived biosensor antagonism. As this confound could not be eliminated with standard isosbestic controls, we propose a simple correction strategy. As a first application, we used the probe to test a proposed mechanism for focal modulation of noradrenergic signaling in and by cortical circuits receiving afferents from the locus coeruleus. We found that increasing spiking activity in CA1 amplifies noradrenergic signaling evoked by contextual arousal by [~]50%, but does not induce norepinephrine release in the absence of a phasic trigger - thus supporting the central prediction of the glutamate amplifies noradrenergic effects (GANE) hypothesis. The P-DOpE probe thus enables optogenetic manipulation and multimodal readout in a configurable low-cost, scalable, and robust format.

neuroscience↗

bioRxiv2026

Super-Resolution Visual ProteomEx for Hard Tissues and Clinical Samples

Correlating nanoscale tissue architecture with unbiased molecular composition within the same specimen remains a fundamental challenge in spatial biology. Current spatial proteomics methods either lack the imaging resolution required to resolve nanoscale tissue architecture or achieve only limited proteome coverage, and untargeted approaches capable of deep protein identification have yet to be integrated with super-resolution imaging within a single workflow. Here, we present microProteomEx, an integrated platform that combines hydrogel-assisted tissue expansion with mass spectrometry-compatible fluorescence imaging, laser capture microdissection, and bottom-up proteomics to achieve simultaneous three-dimensional super-resolution imaging (effective lateral resolution down to [~]47 nm on conventional diffraction-limited microscopes) and spatially resolved proteomics at a scalable lateral resolution of 29-100 {micro}m (0.02-0.28 nL volumetric resolution). By optimizing fixation, protein anchoring, and a secondary re-embedding strategy, we extend the method to mechanically resilient tissues, including mouse kidney and heart, as well as to formalin-fixed, paraffin-embedded clinical specimens. We demonstrate single-glomerulus and single-plaque proteomics (450-1,000 proteins per structure), resolve proteomic differences between malignant melanoma and giant congenital melanocytic nevus in a rare pediatric case, and characterize the morphology-resolved molecular heterogeneity of cored versus diffuse amyloid-beta plaques in a mouse model of Alzheimers disease across two disease stages. microProteomEx establishes a broadly accessible framework for correlating tissue ultrastructure with deep spatial proteomics, with direct implications for disease biology, biomarker discovery, and precision medicine.

biochemistry↗

bioRxiv2026

VigExp: A functionally verified platform for aiding cowpea (Vigna unguiculata) and related legume crop improvement

Legumes include some of the worlds most significant crop species, such as cowpea (Vigna unguiculata), a subsistence crop widely grown in sub-Saharan Africa. Despite their importance, legume crop improvement is hindered by a lack of high-resolution expression data, particularly for reproductive tissues and cell types. Here, we report on VigExp, a tool for visualising cowpea gene expression datasets. We demonstrate its utility across a range of vegetative and reproductive cell types of varieties IT97K-499-35 and IT86D-1010, which exhibit 93.75% protein sequence conservation and are amenable to stable transformation. This includes previously published transcriptomes of vegetative, floral and seed tissues, combined with developmentally staged male and female reproductive tissues. Also integrated are novel transcriptomes of laser-captured cell types covering reproductive development from meiosis to early embryo formation post-fertilisation. Spatial expression patterns and transcript levels can be visualised through an electronic fluorescent pictograph (eFP) browser. Validated by RT-qPCR, in situ hybridisation, transgenic, and CRISPR gene editing analyses, the predictive accuracy of VigExp matches prior cowpea functional study observations. Critical genes for nodule development and regulation were also identified and their expression patterns established in cowpea. Novel reference genes, constitutively expressed gene promoters for visualisation markers/gene-editing, and tissue- and cell-specific gene promoters for targeting these regions, were identified. The A-type cyclin, VuTAM2, was also identified, with a critical role in male meiosis established. Collectively, VigExp represents an adaptable and updatable resource to support crop improvement in cowpea and other legumes, which are often highly syntenic with respect to genome composition.

plant biology↗

bioRxiv2026

Species-Specific Roles of RIPK1 and TRADD in TNF-Induced Cell Death Reveal a Translational Gap Between Mouse Models and Human Biology

Mouse models have historically been central to studies of TNF-induced cell death and guided pharmaceutical translation into clinic, based on the assumption that TNF signaling is conserved between human and mouse. Here, our work uncovers critical species-specific differences between the two. By systematically dissecting the roles of RIPK1, TRADD, and sensitivity to RIPK1 inhibitors in TNF signaling--including RIPK1 kinase-dependent and-independent apoptosis--we found that both apoptosis modalities diverge between human and mouse cells. In mouse cells, RIPK1 suppresses TRADD-mediated kinase-independent apoptosis, whereas in human cells, RIPK1 and TRADD act redundantly. Moreover, RIPK1 inhibitors block kinase-dependent apoptosis in mouse but not human cells, despite effectively inhibiting RIPK1 S166 phosphorylation. Cross-species complementation revealed that these discrepancies stem not from RIPK1 itself but from cell-context differences. These findings echo the clinical failures of RIPK1 inhibitors despite efficacy in mouse models and underscore the need for humanized models and therapeutics that more faithfully predict clinical outcomes.

Cell Biology↗

bioRxiv2026

mTORC1 Directs TNF-Induced Life-or-Death Decisions via Complex I Destabilization

The transition from tumor necrosis factor (TNF)-induced plasma membrane-bound complex I to cytosolic death-inducing complex II switches cells from survival to death. However, the precise regulation of this fatal decision is incompletely understood. Here, we show that mTORC1 promotes this transition by destabilizing later-stage complex I without affecting its initial assembly. Inhibition of mTORC1 unleashes ATG9A and FIP200 activity, thereby promoting the accumulation of CHUK (IKK) in complex I. CHUK scaffolds the kinase-active IKK{beta} to stabilize complex I and prevent complex II formation. Activation of this ATG9A/FIP200-CHUK/IKK{beta} axis protects against TNF-induced fulminant hepatitis while compromises antibacterial defense against Staphylococcus aureus. This mTORC1-governed life-or-death transition provides therapeutic insight into TNF-related pathologies--including cancer, metabolic tissue injury, and microbial infections--where mTORC1 activity is frequently suppressed.

Cell Biology↗

bioRxiv2026

A cis-regulatory variant in ASIP causes gray coat color in the donkey

BackgroundGray is one of the relatively rare coat colors in donkeys. The Hetian Gray donkey is a distinctive indigenous breed from the Xinjiang Uygur Autonomous Region of Northwestern China, characterized by progressive hair depigmentation with aging while retaining dark skin pigmentation. However, the genetic basis underlying this unique gray coat color phenotype remains unclear. ResultsTo elucidate the genetic basis, we conducted whole-genome resequencing of Gray and non-Gray donkeys. Genome-wide selection signature analyses identified a candidate region on chromosome 15. Subsequent fine-mapping using mass spectrometry-based genotyping of 42 loci refined the candidate interval and revealed a SNP within intron 2 of the ASIP gene, located in a genomic fragment with highly similar sequences, showing complete association with the gray coat color. Association analysis in an expanded population further confirmed a strong correlation between this variant and the gray phenotype. Gene expression analyses also supported the role of ASIP in regulating pigmentation in donkeys. ConclusionsThese findings identify a genetic determinant of gray coat color in donkeys and provide new insights into the molecular mechanisms underlying age-related depigmentation in domestic animals.

genomics↗

bioRxiv2026

eRNAformer enables genome-wide de novo mapping of enhancer-derived RNA loci

Enhancer-derived RNAs (eRNAs) are critical regulators of gene transcription, yet their genome-wide annotation remains challenging. Here, we present eRNAformer, a multi-modal deep learning framework that integrates convolutional neural networks with transformers, specifically designed to capture long-range genetic features associated with bidirectional transcription. This approach enables de novo mapping of eRNA loci using DNA sequence and aggregated conventional RNA-seq data. When evaluated on ENCODE datasets, eRNAformer demonstrated high sensitivity and specificity in discriminating known eRNA loci from non-eRNA loci. Notably, the newly identified eRNA loci were enriched with evolutionarily constrained variants and genetic risk factors for complex diseases, and exhibit potential relevance for cancer therapy. Applied to GEO datasets, eRNAformer identified a range from 14,219 to 56,451 eRNA loci across multiple hematologic malignancies, facilitating the construction of a comprehensive eRNA database for blood cancers. We further identified and experimentally validated FOXO1e, a cluster of eRNAs located approximately 120 kb upstream of FOXO1, a known oncogene that drives t(8;21) acute myeloid leukemia (AML) preleukemic program. Together, these findings establish eRNAformer as a powerful tool for genome-wide eRNA annotation, provide a valuable resource for eRNA studies in hematologic cancers, and underscore the functional importance of eRNAs in AML pathogenesis.

bioinformatics↗