Biology subjects

Wang, F.

Publications and source records attributed to Wang, F..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

O-GlcNAcylation-Ubiquitin Crosstalk of METTL1 Drives m7G Epitranscriptomic Collapse and Lipid Metabolic Reprogramming in Diabetic Cardiomyopathy

BackgroundMetabolic remodelling and memory in cardiomyocytes is a pivotal mechanism underlying cardiomyopathy pathogenesis. Clinical observations demonstrate persistent progression of hyperglycaemia-induced multiorgan damage following blood glucose stabilization, which is predominantly mediated through epigenetic regulation. While prior studies have identified epigenetic contributions to hyperglycaemic myocardial injury, the involvement of RNA methylation-particularly N7-methylguanosine (m7G) modification-in this regulatory network remains undefined. MethodsClinical specimens were collected from diabetic patients, and cardiomyocyte-specific METTL1 and ob/ob knockout murine models were established in parallel. Multiomic profiling (proteomics, glycoproteomics, ubiquitinomics, m7G-MeRIP sequencing, and metabolomics) was systematically conducted. The molecular mechanisms governing METTL1 regulation via O-GlcNAcylation and ubiquitination were elucidated through integrated in vitro and in vivo assays. A DUB siRNA library and computational strategies combining molecular docking with molecular dynamics simulations were employed for screening drugs targeting METTL1 O-GlcNAcylation, followed by in vivo therapeutic validation. ResultsComparative analysis of diabetic murine and human samples revealed strong METTL1 downregulation in cardiomyopathy contexts. Tamoxifen-inducible METTL1 knockout mice presented exacerbated diabetic cardiomyopathy phenotypes, confirming its cardioprotective function. Multiomic integration demonstrated that METTL1-mediated m7G modification critically regulates cardiomyocyte fatty acid metabolism. Mechanistically, hyperglycaemia was found to induce O-GlcNAcylation at the METTL1-T268 residue, suppressing m7G methyltransferase activity by 38% (p < 0.01). Subsequent investigations revealed that USP5 deubiquitinase activity is impaired under hyperglycaemic conditions, leading to accelerated METTL1 degradation. Notably, administration of the first-in-class small drug HIT106265621 significantly attenuated cardiomyopathy-associated pathological alterations in ob/ob mice in vivo. ConclusionHyperglycaemia promotes METTL1 O-GlcNAcylation, which impedes USP5-mediated deubiquitination, consequently reducing cardiomyocyte METTL1 protein levels and m7G modification. METTL1 deficiency drives diabetic cardiomyopathy progression through fatty acid metabolic dysregulation, inflammatory activation, and myocardial hypertrophy. Pharmacological inhibition of the OGT-METTL1 interaction using HIT106265621 has therapeutic potential for metabolic cardiomyopathy intervention.

pathology↗

bioRxiv2025

Interwoven DNA-MOF crystals for multi-millennial data storage

DNA has emerged as a promising medium for high-density and energy-efficient data storage, providing a promising solution to capacity constraints and energy demands resulting from the exponential growth of data. Long-term stable storage of DNA data in ambient conditions is a critical requirement for its practical application. Whereas strategies have been proposed to protect DNA from environmental degradation, they are often at the expense of data storage density. Here, we propose a strategy via interweaving metal-organic framework (MOF) and DNA to synthesize DNA-MOF crystal (DNA-MOF), a high-density and long-lifespan DNA-based information material. The uniform distribution of DNA molecules within the crystalline frameworks enables a high loading capacity of up to 30 wt%, corresponding to a theoretical information density of 106.6 exabytes/g. The crystal structure of MOF-DNA demonstrates efficient resistance to environmental damage such as heat, ultraviolet radiation, DNase, etc., achieving an estimated archival half-life over 24,000 years at 9.4 {degrees}C. The interwoven DNA-MOF crystals establish a material foundation for the reliable operation of DNA storage systems in open-field deployment and provide a new pathway toward sustainable long-term management of massive data.

biochemistry↗

bioRxiv2025

Visual-like Template Diffusion: Boosting Single-Sequence Protein Structure Prediction by Adapting Image Diffusion Models

Single-sequence protein structure prediction has drawn increasing attention due to the high computational costs associated with obtaining homologous information. Here, we propose a visual-like 2D geometric template* diffusion method, named TDFold, to generate high-quality pairwise geometries (including pairwise distances and orientations) for achieving accurate and highly efficient single-sequence 3D structure prediction for proteins. Given a protein sequence, TDFold initially generates high-quality inter-residue geometries from a probabilistic diffusion perspective. Since inter-residue geometries can be encoded as multi-channel feature matrices, analogous to image feature maps, we construct an image-level 2D geometric template diffusion module by adapting the stable diffusion (SD) model from text-vision generation to sequencegeometry diffusion for proteins. Subsequently, a lightweight sequencegeometry collaborative learning (SCL) network is constructed to facilitate accurate and efficient protein structure prediction. As a result, TDFold possesses three highlights: (i) better single-sequence prediction performance: TDFold greatly outperforms existing protein language models (PLMs, e.g. ESMFold and OmegaFold) and homology-based methods (e.g. AlphaFold2, AlphaFold3 and RoseTTAFold) on homologyinsufficient datasets such as Orphan and Orphan25, while also achieving promising results on the popular CASP14, CASP15 and CASP16 benchmarks; (ii) low resource consumption: By utilizing the lightweight SCL architecture, the GPU memory consumption of TDFold is generally lower than that of popular methods such as AlphaFold2 and ESMFold; (iii) higher efficiency in training and inference: TDFold can be trained within a week using a single NVIDIA 4090 GPU. Furthermore, the inference time of TDFold is significantly shorter (about 10x to 100x) than that of existing methods (ESMFold, AlphaFold2 and AlphaFold3) for long protein sequences. This work demonstrates the effectiveness of leveraging powerful vision diffusion models to enhance protein 2D geometric template generation, thereby establishing a new paradigm for single-sequence protein structure prediction. It also accelerates protein-related research, particularly for resource-limited universities and academic institutions. The code has been released to speed up biological research.

bioinformatics↗

bioRxiv2025

Detection of Region-specific Fiber Damage within Injured Spinal Cord Using Advanced Diffusion MRI

This study aimed to evaluate diffusion parameters derived from diffusion tensor imaging (DTI) and spherical mean technique (SMT) for detecting region-specific, fine-grained tissue damage and white matter (WM) tract disruptions following spinal cord injury (SCI). Diffusion MRI data were acquired from the cervical spinal cord of monkeys before and after a unilateral dorsal column lesion at the C5 level, using a 9.4T scanner. Parametric maps derived from DTI and SMT effectively detected regional fiber damage around 16 weeks post-injury. Post-mortem silver staining served as the ground truth for assessing region-specific fiber damage. Diffusion MRI maps aligned well with histological measures and captured the severity of WM damage at the lesioned segment (in an order of dorsal > ventral > lateral WM tracts) and along the dorsal column tract across segments (in an order of lesion center > rostral > caudal). Among the diffusion parameters, fractional anisotropy (FA), axonal volume fraction (Vax), radial diffusivity (RD), and extra axonal transverse diffusivity (Dex) showed most significant changes at and around the lesion site where severe tissue damage occurred. FA, Vax, and axial diffusivity (AD) exhibited marked changes in dorsal column proximal to the lesion center, where moderate axonal damage occurred. Additionally, AD and FA showed the greatest sensitivity (true positive rate) and specificity (true negative rate) to mild fiber disruption and demyelination in regions distal to the lesion. Overall, FA provided the highest sensitivity and specificity for detecting fiber degeneration and demyelination, while Vax demonstrated the strongest spatial correlation with histologic markers of regional fiber damage. The combination of DTI and SMT thus offers reliable biomarkers for assessing SCI.

neuroscience↗

bioRxiv2025

Early Detection of Neuroinflammation and White Matter Damage Following Dorsal Spinal Nerve Root Sectioning in a Nonhuman Primate Model

PurposeDorsal rhizotomy, or spinal dorsal nerve root lesioning, is a surgical procedure used to treat intractable nerve pain by selectively severing sensory afferent nerve roots. This study aimed to evaluate whether multiparametric MRI, including diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT), and chemical exchange saturation transfer (CEST), can sensitively detect structural and biochemical changes in the intact spinal cord following a focal dorsal nerve root section in a non-human primate model. MethodsIn four squirrel monkeys, unilateral dorsal nerve roots at cervical segments C4 and C5 were surgically transected. MRI data were collected using a 9.4 T scanner with a custom saddle-shaped transmit-receive quadrature coil before and one week after lesioning. DTI-derived fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD); qMT-derived pool size ratio (PSR); and CEST and nuclear Overhauser enhancement (NOE) effects were quantified across seven spinal cord regions of interest (ROIs). CEST and NOE effects were extracted using five-pool Lorentzian fitting of Z-spectra. ResultsAt the lesioned dorsal nerve root bundles, FA, PSR, and NOE (-1.6 ppm) values decreased, while RD and CEST (3.5 ppm) increased, consistent with fiber degeneration, demyelination, and inflammation. Similar, though less pronounced, changes were observed in the dorsal root entry zone, particularly within the first week post-lesion. ConclusionMultiparametric MRI enables region-specific detection of early spinal cord pathology as soon as one week following dorsal nerve root injury. These findings support its potential as a noninvasive tool for monitoring secondary degeneration due to spinal nerve damage and for evaluating outcomes of therapeutic interventions.

neuroscience↗

bioRxiv2025

Floral innovation through modifications in stem cell peptide signaling.

Understanding how evolution shapes genetic networks to create new developmental forms is a central question in biology. Asteraceae (sunflower family) comprise 10% of flowering plants and have capitula, a novel flowering shoot (inflorescence) that mimics a single flower (1, 2). During capitulum development, shoot stem cells undergo prolonged proliferation relative to other species (3, 4). Here we show that capitulum evolution paralleled decreases in CLAVATA3 peptide (CLV3p) signaling, a conserved repressor of stem cell proliferation. Asteraceae CLV3p displays reduced receptor binding and downstream transcriptional outputs. Reversion of CLV3 to a more active form impairs Asteraceae stem cell regulation and capitulum development. Lastly, we trace CLV3 evolution across the Asterales allowing inferences on capitulum evolution. Our findings reveal novel evolutionary mechanisms in plant reproduction and suggest approaches for engineering crops.

plant biology↗

bioRxiv2025

In vivo Calcium Imaging in the Near-Infrared II Window

Non-invasive deep-tissue calcium imaging of live mammals with high sensitivity and resolution is challenging owing to light scattering experienced by traditional calcium ion (Ca2+) indicators with excitation and emission wavelengths within 400-750 nm. Here, we report near-infrared II (NIR-II) calcium imaging beyond 1000 nm by exploring a natural protein derived from a bacterium (Thermochromatium tepidum) living in a calcium carbonate-rich environment. This highly photostable fluorescent protein enables NIR-II imaging of intracellular Ca2+ responses to stimulant drugs in cultured mammalian cells with sensitivity comparable to that of visible Ca2+ indicators. We achieve in vivo NIR-II imaging of Ca2+ transients in response to two different tumor treatment strategies in intact tumors with high sensitivity, resolution, and contrast, opening the possibility of non-invasive deep-tissue calcium imaging for assessing treatment efficacy longitudinally. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/661443v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@149504eorg.highwire.dtl.DTLVardef@37722borg.highwire.dtl.DTLVardef@2878a7org.highwire.dtl.DTLVardef@1091d0c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Pentose Sugars Encode Sequence-Dependent DNA-RNA Segregation for Biomimetic Multiphase Condensates

The nucleus segregates DNA and RNA with high precision to safeguard genome stability and gene regulation despite their homologous structures, yet the underlying molecular principles have long evaded both understanding and synthetic translation. Here we show that a single atomic difference between the pentose sugars, a 2-OH in RNA versus a 2-H in DNA, suffices to drive their phase segregation with cationic peptides. This subtle chemical distinction makes RNA bind peptides more strongly than sequence-identical DNA, generating an asymmetry that, when modulated by sequence-encoded homotypic interactions, drives the formation of core-shell multiphase condensates. Using a supervised machine-learning approach, we distill these molecular principles into a predictive design rule and harness it to program a library of oligonucleotide pairs, termed SEGREGamers, that self-assemble into droplets with coexisting DNA- and RNA-rich domains. These synthetic condensates recapitulate nuclear compartment functions, including selective molecular partitioning and enhanced RNA catalysis. Our results establish a chemically encoded platform for engineering synthetic nuclear mimics and programmable biomolecular condensates, and suggest that sugar identity may have served as an ancient physical mechanism for organizing nucleic acids.

biophysics↗

bioRxiv2025

An atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2025

Bacteriophage diversity declines with COPD severity in the respiratory microbiome

Chronic obstructive pulmonary disease (COPD) severity correlates with airway microbial dysbiosis, yet bacteriophage roles remain unexplored. We characterised the lung virome by re-analysing 135 sputum metagenomes from 99 COPD patients and 36 healthy controls. We identified 1,308 viral operational taxonomic units, revealing progressively lower viral diversity correlating with disease severity. Whilst viral and bacterial diversity typically showed strong positive correlations, patients with frequent exacerbations uniquely exhibited decoupled viral-bacterial relationships, indicating disrupted ecological dynamics. Phages infecting anaerobic oral bacteria showed disproportionately lower abundance--Porphyromonas phages were 40-fold less abundant despite only 4-fold lower bacterial abundance--whilst pathogen-associated phages showed no significant differences. We detected virulence factor-encoding phages, including two neuA-carrying Haemophilus phages in 7.4% of Haemophilus-colonised patients, associated with 82-fold higher bacterial abundance. These findings establish altered bacteriophage ecology as an unrecognised feature of COPD pathobiology, with differential phage-bacteria relationships that reshape lung microbial ecosystems, offering new perspectives for microbiome-targeted interventions.

microbiology↗

bioRxiv2025

Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2/Gli1/Sf1 signaling axis

Desert Hedgehog (Dhh) mutations cause Leydig cell dysfunction, yet the mechanisms governing Leydig lineage commitment through Dhh-mediated receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, using CRISPR/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh/Patched 2 (Ptch2)/Glioma-associated oncogene homolog 1 (Gli1)/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (Oreochromis niloticus). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of ptch1 and ptch2 in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where ptch2 mutation did not impair testicular development, yet completely rescued the testicular defects in dhh mutants--consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector, and transactivates sf1 expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLCs differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas sf1-mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development. HighlightsO_LIDhh regulates the differentiation of SLCs rather than their survival C_LIO_LIPtch2 acts as the functional receptor for Dhh signaling in SLCs C_LIO_LIGli1 is the principal transcriptional activator for Dhh signaling in SLCs C_LIO_LISf1 is the critical downstream effector of Gli1 in SLCs differentiation C_LI

developmental biology↗

bioRxiv2025

In vivo investigation of STN1 downregulation in melanoma formation in adult mice following UV irradiation

Genome instability is a major force driving tumorigenesis. The ssDNA-binding protein complex CTC1-STN1-TEN1 (CST) plays a pivotal role in maintaining genome stability by countering replication stress, modulating DNA damage repair, and maintaining telomere integrity. Despite its well-documented role in genome maintenance, the involvement of CST in skin cancer development has yet to be investigated. We recently found that CST localizes at stalled DNA replication sites after UV exposure and may suppress the unwanted repriming activity, suggesting a potential role of CST in suppressing genome instability caused by UV damage. In this study, we first analyzed CST expression and alterations in cutaneous melanoma database and found that the CST genes are frequently altered in cutaneous melanoma and their expression is significantly downregulated in melanoma samples compared to normal tissues. We then generated a conditional knockout (cKO) mouse model with STN1 deficiency specifically in melanocytes to investigate its role in skin cancer formation. Upon chronic exposure to UV irradiation, STN1-deficient mice exhibit no obvious difference in melanoma incidence compared to control littermates, suggesting that STN1 downregulation in mature melanocytes has no significant effect on UV-induced skin cancer development in lab mice.

cancer biology↗

bioRxiv2025

DNA framework array enables ultra-high throughput DNA synthesis

High-throughput DNA synthesis has revolutionized synthetic biology, molecular diagnostics, genome engineering, and DNA data storage by enabling the scalable and precise construction of nucleotide-based information systems. However, existing high-throughput synthesis technologies rely on top-down fabrication strategies to maximize throughput, yet they are inherently constrained by physical limitations. These constraints make it exceedingly difficult to achieve single-molecule level synthesis control that is essential for advancing next-generation DNA synthesis. Here, we present a DNA framework-based bottom-up enzymatic synthesis strategy that enables single-molecule level control of DNA synthesis with high-throughput. Leveraging the nanoscale addressability of DNA frameworks, we achieved a synthesis site pitch of 10.9 nm--183-fold smaller than that of previously reported electrode arrays. Theoretical projections suggest that this approach could scale synthesis throughput to 5.3 x 1011 sequences per square centimeter, representing a four-order-of-magnitude improvement over existing synthesis arrays. This approach lays the foundation for gigabyte-scale DNA writing and offers a highly accessible pathway toward large-scale DNA synthesis for emerging applications such as molecular data storage.

synthetic biology↗

bioRxiv2025

Hsp90-dependent triage of the glucocorticoid receptor via the CHIP E3 ubiquitin ligase

The molecular chaperone Hsp90 is required to ensure the proper folding and activation of approximately 10% of the proteome throughout their cellular lifetime1,2. Given that Hsp90 recognizes and preferentially interacts with partially unfolded client states, it is well-poised to promote the degradation of misfolded clients and clients past the point of re-foldability3,4,5. Long- standing phenomenological data suggest that Hsp90 could directly present a client protein to an E3 ubiquitin ligase, in this way mediating degradative ubiquitylation of the client. However, this has yet to be directly demonstrated for any client. To assess this mechanism for the model Hsp90 client the glucocorticoid receptor (GR), a ligand-dependent transcription factor, we reconstituted in vitro the Hsp90-dependent folding cycle for GR6, in the presence of the E3 ligase CHIP. Remarkably, we discovered that CHIP binds to and efficiently ubiquitylates GR as presented by a previously characterized Hsp90-dependent pro-folding state called the GR-maturation state (Hsp90-p23-GR), in which GR has been visualized via cryo-EM to be folded in the native state and ligand-bound7. We determined a low-resolution ([~]14 [A]) cryo-EM reconstruction of the four- component Hsp90-p23-GR-CHIP complex, and furthermore resolved from the same dataset a 3.53 [A] reconstruction of a Hsp90-p23-GR complex in which, surprisingly, GR is partially disordered and ligand-free--in contrast with what we previously observed7, presumably as a consequence of interaction with CHIP. Our results suggest a mechanism by which Hsp90 can simultaneously partition a client between both folding and degradation outcomes and in this way directly mediate protein-triage decisions through its interactions with E3 ligases.

biochemistry↗

bioRxiv2025

Comparative genomics and transcriptomics on salt tolerance of Vigna luteola

Vigna luteola, a wild legume species, shows remarkable variation in salinity tolerance across its natural habitats, with coastal populations exhibiting high tolerance and riverbank populations being sensitive. This intraspecific variation provides a valuable system for investigating the genetic basis of salt tolerance. A major QTL for salt tolerance was previously identified by crossing salt-tolerant and salt-sensitive accessions, but the responsible genes remain unknown. In this study, grafting experiments between the two accessions revealed that the root plays a primary role in salt tolerance by suppressing Na transport to the shoot. We then conducted root transcriptome analysis and identified four candidate genes located within the QTL and highly expressed under salt stress in the tolerant accession: CBL-INTERACTING PROTEIN KINASE 6 (CIPK6), CAFFEOYL SHIKIMATE ESTERASE (CSE), FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13), and DROUGHT-INDUCED 21 (DI21). Promoter analysis revealed that the CIPK6 promoter contains transcription factor binding motifs unique to the salt-tolerant accession, which may contribute to its high expression under salt stress. These findings suggest that CIPK6 is regulated by cis-regulatory differences and is the most promising candidate for the salt-tolerance QTL. The identified genes in this study provide a foundation for developing salt-tolerant crops in the future.

genomics↗

bioRxiv2025

Disturbed engram network caused by NPTXs downregulation underlies aging-related memory deficits

Engram cells storing specific memories are allocated to separate neuronal ensembles, which preferentially recruit either excitatory or inhibitory inputs to drive precise memory expression. However, how these formed neuronal ensembles maintain their stability, and whether the disturbed stability contributes to aging-related memory deficits remain elusive. Here, we show that neuronal pentraxin1 (NPTX1) facilitates Kv7.2-mediated inhibition of Fos+ensemble hyperexcitability, thereby restricting its response to excitatory inputs from medial entorhinal cortex (MEC) and promoting memory expression in the fear context. Meanwhile, NPTX2 facilitates the perisomatic inhibition of the Npas4+ ensemble by parvalbumin+ (PV+) interneurons, thus preventing fear memory overgeneralization. Pharmacological activation of Kv7.2 or chemogenetic activation of PV+ interneurons repaired memory deficits caused by engram specific NPTXs depletion. Contextual fear memory precision and NPTXs expression in dentate gyrus (DG) engram cells are decreased in aged mice. Overexpression of NPTX1 in Fos+ensemble or AMPAR binding domain of NPTX2 in Npas4+ ensemble rescued memory imprecision. These findings elucidate that the coordination of NPTXs prevents engram ensembles from becoming hyperactive and provide a causal link between engram network destabilization and aging-associated memory deficits.

neuroscience↗

bioRxiv2025

Pln1 Mediates Lipid Droplet-Vacuole Tethering During Microlipophagy Saccharomyces cerevisiae

Lipid droplets (LDs) are dynamic organelles that undergo growth or degradation depending on the metabolic state of the cell. One form of LD degradation is autophagy-mediated, referred to as lipophagy. Here, we demonstrate that Pln1, a perilipin located on the surface of LDs in Saccharomyces cerevisiae, previously known for its role in LD biogenesis, is essential for lipophagy. Pln1 facilitates the docking of cytosolic LDs to vacuoles, the lysosome-like organelles responsible for LD degradation, under various nutrient conditions. Molecular dissection of Pln1 revealed that the N-terminal PAT (Perilipin (PLN1), Adipophilin (PLN2), and TIP47 (PLN3)) domain and a hydrophobic region are critical for the localization and binding of LDs to vacuoles. Site-specific mutagenesis within the PAT domain identified a semi-hydrophobic LD Interacting Motif (LIM), which is vital for this interaction. Furthermore, an intrinsically disordered region (IDR) near the center of Pln1 is required for efficient LD-vacuole tethering. These findings support a model in which Pln1 bridges LDs and vacuoles by simultaneously interacting with both organelles. Notably, deleting PLN1 did not impair survival during prolonged nitrogen starvation and enhanced viability in autophagy-defective (atg8{Delta}) cells, suggesting that balancing Pln1-mediated LD biogenesis and lipophagy is crucial for yeast survival under starvation conditions.

cell biology↗

bioRxiv2025

Regenie.QRS: computationally efficient whole-genome quantile regression at biobank scale

Genotype-phenotype associations can be context-dependent and dynamic in nature leading to heterogeneity of genetic effects across different parts of the phenotype distribution. Quantile regression, an alternative to linear regression for continuous phenotypes, is particularly well suited for detecting and characterizing heterogeneous genotype-phenotype associations. Here we propose a novel and computationally efficient whole-genome quantile regression technique, Regenie.QRS, for biobank-scale GWAS data with genetic structure. Our approach first estimates the polygenic effect, and then incorporates this effect as an offset in the non-mixed quantile regression model. Our simulations demonstrate robust control of type I error and higher power to detect heterogeneous associations relative to linear regression in GWAS, and improved power over the marginal quantile regression tests. We present applications using data from the UK Biobank and the ProgeNIA/SardiNIA project, where we show the advantages of Regenie.QRS in identifying and characterizing heterogeneous genetic effects. To cite just one interesting example, using quantile regression we are able to show that even though variants at the G6PC2 locus increase glucose levels, their effects are much stronger at lower quantiles of glucose level distribution than at higher quantiles, showing that G6PC2 serves as a guardian against low glucose levels without driving dangerous hyperglycemia, which may explain the lack of association with diabetes risk.

bioinformatics↗