Biology subjects

Gao, W.

Publications and source records attributed to Gao, W..

At least 19 recordsLinked to original sources

bioRxiv2026

LNP Delivery of Prime Editors Enables Durable Correction of PAH R408W in Phenylketonuria Models

Phenylketonuria (PKU) is a monogenic metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, the most common of which is c.1222C>T (p.R408W). Current treatment options, including dietary restriction and enzyme substitution, can be effective but are often challenging for patients to maintain and do not address the underlying genetic defect. Gene editing represents a compelling one-time treatment approach for PKU. Herein, we demonstrate mRNA:LNP-mediated delivery of prime editors that enable therapeutically-relevant levels of correction of the R408W mutation in both in vitro and in vivo model systems. Further, we found that co-delivery of the DNA repair modulator RAD18 and engineering of the prime editor protein, enabled 2-fold and 3-fold increases in prime editing relative to PE3 respectively, resulting in ~50% correction efficiency in a humanized PKU mouse model. Collectively, this work identifies novel potential approaches to enhancing prime editing and establishes LNP-delivered prime editing as a mutation-specific, non-viral therapeutic strategy for PKU, as well as providing a framework for extending prime editing to other inherited liver diseases.

pharmacology and toxicology↗

bioRxiv2026

Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury

Regulatory T cells (Tregs) are key mediators of immune resolution and tissue repair following acute kidney injury (AKI), yet strategies to selectively enrich Tregs within the renal microenvironment remain limited. Interleukin-2 (IL-2) is essential for Treg survival and function, but systemic IL-2 delivery is constrained by a short half-life, narrow therapeutic window, and risk of off-target activation of cytotoxic T cells. Effective Treg-based immunomodulation may therefore require both localized cytokine signaling and targeted recruitment of precursor immune populations. Here, we present a sequential, biomaterial-based immunomodulatory strategy that integrates immune cell recruitment with sustained cytokine delivery. An injectable granular hydrogel physically encapsulating the chemokine CCL21 was used to initially recruit CD4+ T cells to the injured kidney. Subsequently, supramolecular guest-host interactions were leveraged to deliver IL-2 modified with the hydrophobic "guest" moiety adamantane, enabling prolonged local cytokine release over 28 days. In healthy mice, we observed early CD4+ T cell recruitment, followed by a pronounced increase in Treg frequency, consistent with immune reprogramming driven by our sequential delivery system. In a murine model of bilateral ischemia-reperfusion (BiAKI), this injectable biomaterial induced a local increase in the proportion of FOXP3-expressing Tregs and a concomitant decrease in the levels of AKI markers. This two-step immunomodulatory approach minimizes acute immune activation while promoting long-term enrichment of Tregs within the renal microenvironment. Together, these findings demonstrate that granular hydrogels with supramolecular host capability can orchestrate immune recruitment and differentiation in a spatiotemporally controlled manner, providing a versatile immunomodulatory platform for applicability in kidney disease.

bioengineering↗

bioRxiv2026

Regulatory-scale stripe analysis from single-cell Hi-C with scStripe

Chromatin stripes are a directional architectural feature of three-dimensional genome organization, but their analysis in single-cell Hi-C (scHi-C) at regulatory resolution is hindered by extreme sparsity. We developed scStripe, an imputation-free two-stage statistical framework that detects stripes from sparse cell-type--aggregated scHi-C maps and directly quantifies the resulting aggregate-defined stripes in raw individual-cell contact maps using per-cell stripe scores. Across three complementary benchmark settings, scStripe achieved the highest F1 scores and showed strong aggregate stripe enrichment, while the detected stripes recapitulated characteristic structural and regulatory features reported in bulk data. Per-cell stripe scores resolved recurrent configurations of the EBF1-anchored stripe, captured genome-wide variation associated with cell type, cell-cycle phase, and developmental stage, and identified positively associated gene--stripe pairs with pronounced cell-type specificity using matched scRNA-seq. Together, scStripe provides a practical, scalable framework for regulatory-scale stripe analysis across single cells without requiring single-cell enhancement or 3D reconstruction.

genetics↗

bioRxiv2026

tTEscanR: A user-friendly integrative R package for quantifying and visualizing translation efficiency from sequencing data in diverse biological systems

Translation elongation relies on accurate codon-anticodon pairing. Here, we present tTEscanR, an R package designed to investigate this translational interface. By quantifying mRNA codon demand alongside tRNA anticodon availability, tTEscanR provides scalable estimates of translation rates directly from standard transcriptomic and chromatin accessibility count matrices, where genomic features are represented as rows and experimental conditions as columns. tTEscanR seamlessly integrates into existing bulk and single-cell pipelines and provides modular functions for quality control, filtering, normalization, statistical analysis, and visualization. A structured data object centralizes workflow outputs and associated metadata. A built-in multilevel visualization module generates customizable, publication-ready graphical outputs to facilitate data interpretation and reproducibility of the complex translational landscape. We demonstrate the utility of tTEscanR across cancer biology, aging, and neurodegeneration datasets, uncovering critical translational regulatory programs overlooked by conventional analyses. tTEscanR is available in an open-source repository as a standalone tool or workflow plug-in.

genomics↗

bioRxiv2026

Metagenomic and metabolomic analysis of a bryozoan-associated microbial complex from the Hanjiang River, China

Background Bryozoans are ancient colonial animals that have existed for over 470 million years and are widely distributed across aquatic environments. Recently, many spherical colloids (average diameter{approx}1 meter in diameter), containing bryozoans and diverse microorganisms, were found in the Hanjiang river in China. In this study, we investigated these bryozoan-dominated microbial complexes using metagenomic sequencing, metabolomic profiling, and complementary approaches. Results The results revealed that the microbial structure dominated by bryophytes included eukaryotes such as fungi, microalgae, and small parasites etc., as well as prokaryotes such as bacteria and viruses. All members form a highly integrated consortium that collaboratively maintains community function and stability, which displayed the shape and structure of a regular microbial complex and increased in size. Additionally, the results suggested the predominately presence of Proteobacteria were particularly abundant and are known to produce bryostatins in response to bryozoan signals. Interesting, it was implied that a decrease or even a loss in virulence occurs when pathogenic microorganisms become members of the complex. This is the first study focusing on the composition and metabolites of the unusual microorganism complex. The results discovered the close and intriguing connections within the microbial communities dominated by the ancient organism bryozoan through multi-omics technologies. It showed that both eukaryotes and prokaryotes can coordinate or compete, thereby forming a stable composite structure.

zoology↗

bioRxiv2026

BioMetAll v2.0: Introducing Scores, Metal Discrimination, and Side-Chain Descriptors for Predicting Metal-Binding Sites in Proteins.

Predicting the location of metal-binding sites in proteins is crucial for fundamental biological questions and biotechnological applications. Over the past decade, the rise in metal-bound protein structures in the Protein Data Bank, combined with advanced statistical models such as deep learning, has accelerated the development of metal-binding site prediction tools. Several approaches are now available, offering high-quality benchmarks and predictive performance. Our initial development in this area is BioMetAll, whose first version was based on backbone pre-organization. Here, we introduce its second version, featuring two major updates: 1) metal-specific scoring functions and 2) prediction using backbone geometry alone or in combination with first coordination sphere descriptors. Apart from demonstrating metal sensitivity and yielding better benchmarking results, this new version allows the assessment of the influence of considering the metals first coordination sphere versus backbone pre-organization on how metallic species bind to proteins.

bioinformatics↗

bioRxiv2026

Epigenetic age acceleration is associated with contaminant exposure in common dolphins (Delphinus delphis)

Metals and per- and polyfluoroalkyl substances (PFAS) represent a significant environmental concern, yet their association with epigenetic age acceleration (EAA) remain largely understudied in marine mammals. Here, associations between EAA in common dolphins (Delphinus delphis) and life history (sex and sexual maturity), trace metals, and PFAS were investigated. EAA was calculated as the residual in the regression of epigenetic age vs chronological age, hence providing a direct measure of the deviation of the epigenetic age of an organism (positive or negative) by comparison with expectation, given their actual chronological age. Sixteen trace elements were quantified in hepatic and renal tissues (n = 53). In addition, 28 PFAS were quantified in hepatic tissue (n = 58). Associations between EAA and explanatory variables were assessed using regression-based and multivariate modelling approaches (linear models and canonical analysis of principal coordinates). No effect of sex was observed, although sexual maturity did significantly increase EAA. Exposure to metals was significantly associated with EAA, explaining 55.4% of the variation, with hepatic metals (Se, Zn, Cu, Al, Mn) driving this relationship. Although EAA was not significantly related to the total PFAS exposure overall, a subset of PFAS variables (PFBA, PFDA, PFHxS-B, PFNA) showed significant association with EAA after adjusting for sex and sexual maturity. Together, these subsets of metal and PFAS variables, in addition to the selenium-to-mercury (Se:Hg) molar ratio, explained 66.7% of the variation in EAA. Our results identify sexual maturity and specific contaminant mixtures as key potential drivers of EAA in common dolphins, highlighting the possible use of EAA as a biomarker of environmental and physiological stress in marine mammals.

zoology↗

bioRxiv2026

An LSEC-focused computational drug repurposing platform for liver fibrosis: Identification of vorinostat and other LSEC-protective candidates

Liver sinusoidal endothelial cells (LSECs) are increasingly recognized as a critical yet underexplored cell type in anti-fibrotic drug development. This study presents a computational drug screening platform integrating LSEC-specific transcriptomic analysis across simple steatosis, fibrotic nonalcoholic steatohepatitis (NASH), and cirrhosis, with tiered gene signature selection combining machine learning, large language model-assisted curation, gene safety assessment, and Connectivity Map-based screening using human endothelial perturbational profiles. The platform identifies 6 clinical-stage and 8 preclinical candidates with LSEC-protective potential. Among these, vorinostat (SAHA), a clinically approved histone deacetylase (HDAC) inhibitor, is selected for experimental validation. In hepatocyte-specific Asah1-deficient mice fed a Paigen diet, SAHA attenuates hepatic inflammation, fibrosis, LSEC dysfunction, and portal hemodynamic abnormalities, with effects confirmed in a hepatotoxin (CCl4)-induced fibrosis model. High mobility group box 1 (HMGB1) is identified as a key hepatocyte-derived paracrine mediator of LSEC injury through Transwell co-culture and glycyrrhizin rescue. Vorinostat dose-dependently reverses HMGB1-induced LSEC dysfunction across inflammation, capillarization, fibrogenesis, and vasoconstriction, associated with endothelial transcription factor reprogramming including KLF2 upregulation, validated in primary LSECs and in vivo. SAHA also protected LSECs from TNF--induced inflammation and reduced monocyte adhesion. These findings establish an LSEC-focused drug repurposing framework and identify candidates for LSEC-protective anti-fibrotic therapy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/727430v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@41e95dorg.highwire.dtl.DTLVardef@1401031org.highwire.dtl.DTLVardef@e72fc4org.highwire.dtl.DTLVardef@1f11347_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Wheat MYB transcription factor TaMYB83-7B regulates seed dormancy by influencing the balance between abscisic acid and gibberellin

In wheat, weak seed dormancy (SD) is related to an increased tendency for pre-harvest sprouting (PHS), which reduces yield and quality. However, the molecular mechanism underlying SD remains elusive. Here, we identified a wheat R2R3-MYB transcription factor (TaMYB83-7B) related to SD. Expression analysis showed that TaMYB83-7B was highly expressed in wheat seeds, and was more highly expressed in strong-dormancy varieties than in weak-dormancy varieties. Sequence and association analysis indicated that T/C mutations at -907 bp and -1133 bp in the TaMYB83-7B promoter were significantly associated with wheat SD, with C at both sites related to strong dormancy. Dual-luciferase reporter assays demonstrated that the transcriptional activity of the TaMYB83-7B promoter was significantly higher in strong-dormancy varieties than in weak-dormancy varieties. Further analyses indicated that TaMYB83-7B functions as a transcriptional inhibitor. Germination experiments revealed that overexpression of TaMYB83-7B significantly enhanced SD, while its loss-of-function reduced SD. Finally, TaMYB83-7B was found to regulate SD by influencing the balance between abscisic acid (ABA) and gibberellin (GA) in wheat seeds. Overall, the results of this study enhance our understanding of the complex regulatory mechanism underlying SD, and provide gene targets and molecular markers for the genetic improvement of PHS resistance in wheat.

molecular biology↗

bioRxiv2026

Coordinated immune architecture underlies durable survival in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterised by profound immune dysfunction and limited response to immunotherapy. Although tertiary lymphoid structures (TLSs) are associated with improved outcomes, most studies focus on their presence or density, providing limited insight into how their organisation contributes to tumour control. Here, we analyse a unique cohort of treatment-naive PDAC patients enriched for exceptionally rare long-term survivors (LTS, n = 23; >5-year survival) alongside more common short-term survivors (STS, n = 24), enabling direct interrogation of mechanisms underlying durable tumour control. We develop a multi-scale spatial framework integrating multiplex imaging, computational modelling, and transcriptomics to quantify TLS architecture. By modelling TLSs as higher-order immune assemblies, we define their structural states, spatial organisation, assembly rules and tissue context-dependency within the tumour microenvironment. We show that long-term survival is associated with organised, spatially integrated TLSs exhibiting coordinated B and T cell zoning, whereas short-term survival is characterised by disorganised, Treg-enriched, and spatially isolated TLSs, despite similar immune cell abundance. These architectural differences align with transcriptional programmes: LTS tumours display coordinated lymphoid and NF-{kappa}B-driven chemokine signalling, while STS tumours exhibit inflammation uncoupled from immune organisation. Together, these findings demonstrate that durable anti-tumour immunity in PDAC is defined by coordinated transcriptional, cellular, and spatial organisation, rather than immune presence alone. This study provides a blueprint for structure-informed strategies to reprogram the tumour microenvironment and improve outcomes in PDAC. Statement of significanceIntegrating multiplex imaging, computational modelling and transcriptomics in treatment-naive PDAC enriched for exceptional survivors shows that durable tumour control is associated with organised TLS architecture rather than immune abundance alone, providing a framework for immune-architecture-based biomarkers and therapeutic reprogramming.

cancer biology↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Spatial mapping of RNA turnover kinetics and regulatory landscapes of mRNA stability in the mammalian brain

Spatial and activity-dependent gene regulation in the mammalian brain requires coordinated control of RNA synthesis and degradation 1,2, yet spatially resolved measurement of RNA turnover kinetics in complex tissues remains technically challenging 3. Here, we present spatial NT-seq, an approach that integrates transgenesis-free metabolic RNA labeling with in situ chemical recoding to spatially co-map RNA abundance and turnover kinetics in the mouse brain. By distinguishing newly synthesized from pre-existing RNAs, this method reveals spatially resolved transcriptional and post-transcriptional responses to electroconvulsive stimulation (ECS), a treatment for refractory depression. We uncover pronounced spatial heterogeneity in RNA turnover, with the dentate gyrus (DG) exhibiting elevated basal RNA turnover and robust ECS-induced responses. These findings reveal a "kinetics scaling" mechanism of coordinated regulation of RNA synthesis and decay, by which DG cells can rapidly remodel their transcript pools in responses to external stimuli or differentiation signals 4,5. Machine learning applied to in vivo RNA kinetics landscapes further identifies sequence features and post-transcriptional regulators underlying region-and cell-type-specific control of mRNA stability. Together, this integrated experimental and computational framework, in vivo Timescope, enables transcriptome-wide mapping of RNA turnover kinetics and the regulatory architecture of RNA stability across spatial and cellular contexts, providing new insights into the spatiotemporal regulation of RNA dynamics in brain function and disease.

genomics↗

bioRxiv2026

GmEBS7a-E2 complex dissociation hyperactivates ERAD to impair plant immunity against Phytophthora pathogens

Endoplasmic reticulum-associated degradation (ERAD) pathways are crucial for maintaining plant development and stress responses. While ERAD has been extensively studied for its role in regulating responses to abiotic stress, its specific manipulation by eukaryotic pathogens stress remains unclear. Here, we reported that soybean GmEBS7a, a plant-specific ERAD component, is targeted and stabilized by a transmembrane domain-containing effector Avh131 from Phytophthora sojae. GmEBS7a enhances plant disease susceptibility by increasing ERAD efficiency and ER stress sensitivity. Mechanistically, Avh131 competitively disrupts the interaction with GmEBS7a and the ubiquitin-conjugating enzyme GmUBC32, reducing ubiquitination of GmEBS7a and subsequent inhibition of its degradation. These findings demonstrate that excessive ERAD triggered by stabilized GmEBS7a and its partnering E3 ligase impairs the plants response to biotic stress. Our study uncovers a fine-tuning of the ER protein-folding capacity to promote infection, thereby expanding our understanding of ER-centered immunity during plant-pathogen interactions.

immunology↗

bioRxiv2026

Curcumin Promotes Myelin Repair after Spinal Cord Injury via Spatially Selective Regulation of CLASP2 Phosphorylation

Spinal cord injury (SCI) remains a devastating neurological disorder, where limited axonal regeneration and inefficient remyelination severely restrict recovery. Although curcumin has recognized neuroprotective properties, its mechanism in myelin repair is unclear. Here, we identify a phosphorylation-dependent cytoskeletal pathway as a key target of curcumin. In a mouse spinal cord transection model, curcumin treatment improved hindlimb motor function, reduced fibrotic scarring, and increased myelin basic protein (MBP) in the injured region. Phosphoproteomic profiling revealed cytoskeletal regulation as a major process affected by curcumin, with CLASP2 emerging as a critical target. Curcumin enhanced CLASP2 phosphorylation at Ser1025, a modification that strengthened Golgi association and increased EB1 distribution at the cell periphery, thereby promoting microtubule anchoring without altering global stability. This spatially selective regulation provides a novel mechanism by which curcumin fine-tunes cytoskeletal organization to support remyelination. Analysis of published single-cell sequencing data further showed CLASP2 enrichment in myelin-forming cells, underscoring its relevance. Unlike prior studies emphasizing anti-inflammatory or antioxidant effects, our findings reveal a defined molecular mechanism linking curcumin to cytoskeletal remodeling and myelin repair, highlighting its potential as a safe and accessible therapeutic candidate for SCI.

cell biology↗

bioRxiv2026

Opposing Autonomic Pathways Link Childhood Trauma to Mental Imagery Deficits

Although childhood trauma alters neurobiological systems supporting emotion regulation and autonomic function, mechanisms linking trauma to mental imagery deficits remain unexplored. Here we examined whether autonomic nervous system symptoms mediate trauma-imagery associations in a general population sample (n = 433). All trauma types showed associations with reduced imagery vividness (r = -.12 to -.23), with emotional neglect and emotional abuse demonstrating the strongest effects. Physical trauma types and emotional abuse correlated with increased autonomic symptoms (r = .35-.38). Parallel mediation analyses revealed that autonomic symptom burden (BPQ ANS subscale), but not anxiety, significantly mediated trauma-imagery relationships through opposing mechanisms. Physical trauma types and emotional abuse showed negative indirect effects through heightened autonomic reactivity, with complete mediation for emotional abuse and physical neglect. In contrast, emotional neglect showed a positive indirect effect through reduced autonomic reactivity (a pattern that emerged when controlling for other trauma types) alongside the strongest direct effect on imagery. These findings demonstrate that childhood trauma impacts mental imagery through distinct autonomic mechanisms--hyperreactive dysregulation for physical/emotional abuse versus hyporeactive blunting for emotional neglect--suggesting autonomic-targeted interventions should be tailored to trauma type.

neuroscience↗

bioRxiv2026

AutoPELSA: an automated sample preparation system for proteome-wide identification of target proteins of diverse ligands

Protein-ligand interactions are fundamental to cellular function and drug discovery, and ligand-modification-free strategies have emerged as powerful tools for proteome-wide interrogation of these interactions. Among these, the peptide-centric local stability assay (PELSA) stands out for its high sensitivity. It uses a single digestion step to detect ligand-induced local stability shifts, enabling precise binding region localization and affinity estimation. However, manual PELSA workflows suffer from multiple labor-intensive steps that introduce variability and constrain throughput, limiting large-scale applications. To address these limitations, we developed AutoPELSA, an automated platform that streamlines the PELSA workflow including the limited proteolysis step and the following peptide separation step. AutoPELSA completes 96 samples in [~]4 h, enabling high-throughput analysis under native conditions. AutoPELSA reliably detected targets of both strong-affinity ligands (e.g., staurosporine, identifying 114 kinase targets) and low-affinity ligands, including -ketoglutarate (30 known targets). Furthermore, a mixed-ligand dose-response strategy enabled simultaneous determination of binding affinities for multiple ligand-protein interaction regions in a single experiment. Overall, AutoPELSA provides a scalable and modification-free platform for proteome-wide identification and affinity profiling of ligand-protein interactions.

molecular biology↗

bioRxiv2026

A cohesin-centric gene regulatory network resource with regulatory site annotations

Cohesin is a central regulator of transcription and chromatin organization, binding to the majority of cis-regulatory elements (CREs) and mediating enhancer-promoter communication through three-dimensional genome architecture. Although gene regulatory networks (GRNs) provide an interpretable framework for modeling transcriptional regulation, most existing GRN analyses focus on transcription factor (TF)-gene relationships and largely ignore regulatory sites. Consequently, cohesin-associated regulatory contexts are rarely incorporated into GRN reconstruction. Here, we present a cohesin-centric gene regulatory network database that explicitly integrates TF binding, regulatory sites, and gene targets into unified TF-site-gene regulatory paths. Building upon our previously developed multiomics resource CohesinDB, we mapped TF binding to cohesin-associated regulatory sites and linked these sites to their downstream target genes. The resulting Cohesin-GRN module in CohesinDB (http://cohesindb.wangjklab.com/) (http://120.24.147.32/)comprises 61,222,502 TF-cohesin site links and 2,228,634 cohesin site-gene links, collectively forming over 270 million TF-site-gene regulatory paths. By enabling a CRE-informed and site-aware representation of gene regulation, Cohesin-GRN bridges conventional TF-gene GRNs with regulatory site-centric mechanisms. Given the pervasive roles of cohesin in enhancer activity, transcriptional control, and human disease, Cohesin-GRN provides a valuable resource for exploring transcriptional dysregulation and gene regulatory networks.

bioinformatics↗

bioRxiv2025

Melody: Decoding the Sequence Determinants of Locus-Specific DNA Methylation Across Human Tissues

DNA methylation is a fundamental epigenetic modification that plays crucial roles in transcriptional regulation, cellular differentiation, and genome stability. However, how locus-specific DNA methylation is determined by intrinsic DNA sequence remains poorly understood. Here, we introduce Melody, a deep learning framework that predicts DNA methylation from 10-kb genomic sequences, enabling the integration of both local and long-range sequence signals. Across 39 human tissues, Melody accurately predicts methylation profiles and consistently outperforms existing state-of- the-art methods in whole-chromosome, hypomethylated-region, and cell-type-specific benchmarks. Melody also generalizes to methylation quantitative trait locus (meQTL) effect prediction and identifies regulatory sequence motifs associated with methylation variability. To extend prediction beyond profiled tissues, we further develop Melody-G, which incorporates single-cell RNA-seq foundation model embeddings to infer methylation states in previously unseen cell types directly from transcriptomic data. Together, Melody provides a unified framework for linking genomic sequence and cellular state to DNA methylation and offers new insights into the regulatory logic governing the human methylome.

bioinformatics↗