Biology subjects

Li, J.

Publications and source records attributed to Li, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2026

FoTO1 is an epoxide isomerase in paclitaxel biosynthesis

Paclitaxel biosynthesis is limited by the instability of taxadiene-4(5)-epoxide, which readily diverts to the non-productive byproduct 5(12)-oxa-3(11)-cyclotaxane (OCT) instead of rearranging to taxadiene-5-ol. Although FoTO1 suppresses OCT accumulation, its molecular function has been unclear. Here we identify FoTO1 as a dedicated epoxide isomerase that directs productive rearrangement. Biochemical characterization, site-directed mutagenesis, and QM/MM calculations reveal a pre-organized D68-D149 dyad that electrostatically activates epoxide ring opening and stereospecific rearrangement. Modular dissection of the C-terminal extension further reveals a functional partition between catalytic integrity and productive coupling with T5OH, mediated by specific hydrophobic contacts that enforce precise geometric complementarity at the binary complex interface. These results demonstrate how electrostatic activation and enzyme association cooperate to control the fate of a highly reactive intermediate in paclitaxel biosynthesis.

biochemistry↗

bioRxiv2026

TRiC folds the giant ciliary protein IFT172 via a non-canonical open-state mechanism

The eukaryotic chaperonin TRiC/CCT is essential for folding complex proteins, yet how it folds substrates that exceed its closed chamber capacity remains a longstanding paradox. Here, we define the folding pathway of IFT172, the largest subunit ([~]200 kDa) of the intraflagellar transport (IFT) machinery, and uncover a "divide-and-conquer" mechanism. TRiC and HSP70 engage IFT172 concurrently but on distinct domains: TRiC captures the N-terminal WD40 {beta}-propellers within its chamber, whereas HSP70 independently stabilizes the C-terminal TPR domain in the cytosol. To accommodate this oversized client, specific TRiC subunits (CCT4, CCT2, and CCT7) undergo pronounced Z-shaped outward bending, thereby expanding the chamber. Unexpectedly, the first WD40 domain reaches a near-folded state within the open, ATP-bound chamber, and subsequent TRiC ring closure triggers substrate ejection rather than encapsulation. This non-canonical "fold-and-eject" mechanism challenges the classical view that the closed chamber is an obligate folding cage. We further demonstrate that this pathway is essential for ciliary functions in vivo, and reveal a conserved mode of chaperonin recognition among IFT components bearing tandem WD40-TPR architectures. Together, our findings establish a new paradigm for the folding of oversized, multi-domain proteins and identify TRiC as a central proteostasis hub in ciliary biogenesis, with direct implications for ciliopathy pathogenesis.

biochemistry↗

bioRxiv2026

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗

bioRxiv2026

Polyclonal-Monoclonal Transition in Lung Squamous Cell Carcinoma Evolution

The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1) and cytoskeletal regulators (e.g., KIF26A). Collectively, these findings established a polyclonal-monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

genomics↗

bioRxiv2026

Population Structure and Antimicrobial Resistance Gene Transfer of Respiratory Escherichia coli Isolated from Swine in China

ABSTRACPorcine respiratory diseases caused by extraintestinal pathogenic Escherichia coli (ExPEC) pose a severe threat to swine production and public health; however, research on respiratory tract-isolated ExPEC remains limited. This study comprehensively analyzed the genomic characteristics and antibiotic resistance gene (ARG) transfer potential of 441 ExPEC strains isolated from porcine lungs across 21 Chinese provinces (including 53 newly isolated strains from 2022-2024 and 388 NCBI-deposited strains). Phylogenetic analysis revealed that 84% of the isolates belonged to phylogroups A, B1, and C, with ST410, ST101, and ST88 as the predominant STs. The strains exhibited extensive ARG diversity, harboring 111 distinct ARG subtypes, with sul2 (81.4%), floR (73.5%), and tet (A) (68.0%) being the most prevalent. Importantly, critical "last-resort" antibiotic resistance genes (e.g., blaNDM-1/5, the mcr family, and tet (X4)) were also detected. Notably, 77.2% of the ARGs presented horizontal transfer potential, with plasmids (especially IncF family replicons) serving as core vectors, followed by integrons and transposons. Cooccurrence network analysis identified aph (3)-Ib, aph (6)-Id, sul2, and floR as core subnetworks driving multidrug resistance dissemination. Pangenomic analysis confirmed an open genome architecture, with core genes accounting for only 6%, reflecting the strains capacity to acquire exogenous genetic material via horizontal transfer. From the One Health perspective, these transferable ARGs can spread to the environment and humans through fecal discharge and the food chain. These findings underscore the importance of monitoring and controlling ExPEC infections in swine, as such strains can as reservoirs of ARGs, pose potential risks to human health, and may even act as sources of pathogenic agents responsible for human infections. IMPORTANCEPorcine respiratory ExPEC-induced diseases threaten swine production and public health, yet respiratory tract-isolated ExPEC research remains scarce. This study comprehensively analyzed 441 porcine lung ExPEC strains across 21 Chinese provinces, uncovering their dominant phylogroups, high ARG diversity (111 subtypes) and the presence of "last-resort" antibiotic resistance genes. We identified 77.2% of ARGs with horizontal transfer potential, plasmids (especially IncF family) as core vectors, and a core ARG subnetwork driving multidrug resistance. The open pangenome (6% core genes) highlights ExPECs strong capacity to acquire exogenous genes. These findings fill the research gap of respiratory ExPEC, clarify ARG transmission mechanisms in swine ExPEC, and provide critical genomic data for One Health-based AMR surveillance and control, guiding targeted strategies to mitigate ARG spread from swine to humans and the environment.

microbiology↗

bioRxiv2026

Coronavirus envelope protein drives iron sensing disorder by hijacking the TAp73-FDXR axis

Iron overload is increasingly recognized as a critical contributor to coronavirus pathogenesis1, yet the underlying induction mechanisms remain unclear. Here, we uncover a fundamental pathway by which coronavirus drives IRP1 RNA-binding activity to induce iron accumulation2 via targeting the TAp73-FDXR axis. Specifically, coronavirus infection represses transcription of FDXR (encoding the key rate-limiting enzyme in host iron-sulfur cluster synthesis3), thereby impairing host iron-sulfur cluster generation to trigger the functional conversion of the cytosolic aconitase 1 (ACO1) into iron-regulatory protein 1 (IRP1)4, ultimately leading to the hosts persistently false perception of iron deficiency. We identify TAp73 as the primary transcription factor governing FDXR expression, and demonstrate that the coronavirus envelope protein (CoV-E) orchestrates TAp73 nuclear export. Subsequently, CoV-E binds TAp73 through a critical valine residue within its C-terminal PBM domain, inducing the K48-linked ubiquitination and proteasomal degradation of TAp73. Furthermore, we developed a CoV-E-targeting molecule, DPTP-FC, which blocks CoV-E-TAp73 interaction via forming steric hindrance and effectively alleviates iron accumulation and tissue damage caused by PEDV, PDCoV, and SARS-CoV-2 infection. Our study reveals the central role of the TAp73-FDXR axis in CoV-induced iron accumulation, highlighting CoV-E as an attractive antiviral target and DPTP-FC as a promising therapeutic candidate.

microbiology↗

bioRxiv2026

Influenza Virus Infection of an Immunocompetent Organotypic Model of the Human Respiratory Mucosa

Respiratory infectious diseases are among the leading causes of global morbidity and mortality and remain a major public health concern. Progress in understanding early host-pathogen interactions has been hampered by the limited physiological relevance of existing experimental systems. Different models mimicking the human respiratory epithelium have been developed to study viral infections in vitro, such as tridimensional (3D) tissue models and organoids. However, many lack key features of human tissue architecture, particularly the lamina propria or immune cells. To address these limitations, we established an immunocompetent 3D model of the human respiratory mucosa by combining nasal epithelial cells isolated from nasal brushings, fibroblasts from mid-turbinate nasal biopsies, and macrophages derived from blood monocytes. These cells were sequentially seeded into collagen-chitosan scaffolds, resulting in a reconstructed respiratory mucosa closely resembling the in vivo nasal tissues. To further confirm the physiological relevance of the model, we infected it with influenza A virus. The mucosa model supported viral replication in the epithelium and consequently showed increased secretion of inflammatory cytokines and upregulation of type I interferon related genes, enabling the monitoring of early antiviral innate immune responses in a physiologically relevant context.

bioengineering↗

bioRxiv2026

Structural basis for saccharide binding by human RNase 2/EDN, a protein combining enzymatic and lectin properties

Human RNase 2 (eosinophil-derived neurotoxin, EDN) is a major eosinophil granule protein of the vertebrate-specific RNase A superfamily and is involved in antiviral response and inflammation. Identifying ligand-binding pockets in EDN is thus relevant to structure-based drug design. In our laboratory we identified by protein crystallography a conserved site at the protein surface binding to carboxylic anion molecules (malonate, tartrate and citrate). Searching for potential biomolecules rich in anion groups and considering previous report of EDN binding to glycosaminoglycans, we explored the protein binding to saccharides. Next, EDN crystals were soaked with mono- and disaccharides, and the 3D structures of ten complexes were solved by X-ray crystallography at atomic resolution. We identified protein binding pockets to glucose, fucose, mannose, sucrose, galactose, trehalose, N-acetyl-D-glucosamine, N-acetylmuramic acid, and the sialic acid N-acetylneuraminic acid. A main site for glucose, fucose, and galactose was located adjacent to the spotted carboxylic anion site. Secondarily, N-acetylneuraminic acid, N-acetylmuramic acid, sucrose, galactose, and mannose shared another protein surface region. Overall, the saccharides clustered into seven defined sites, outlining a conserved recognition pattern, which was further analysed by molecular modelling. Interestingly, within the RNase A family, we find amphibian RNases that were initially isolated as carbohydrate binding proteins and named as leczymes, combining enzymatic and lectin properties. The present data is the first systematic structural characterization of a mammalian sugar-binding RNase within the family. The results highlight unique EDN residues that mediate its sugar specific interactions, of particular interest for a better understanding of the protein physiological role. HighlightsO_LIstructure of RNase 2 in complex with mono and disaccharides at atomic resolution C_LIO_LIidentification of RNase 2 unique sugar binding sites C_LIO_LIcharacterization of a mammalian RNase A family enzyme with lectin properties C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/713198v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1d805f7org.highwire.dtl.DTLVardef@16fcc49org.highwire.dtl.DTLVardef@ccfd92org.highwire.dtl.DTLVardef@1b8f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Diatom Endosymbionts have Shrinking but Stable Genomes Despite Low Coding Density

Successful establishment of long-term, obligate endosymbiotic relationships requires integration of hosts and endosymbionts across multiple levels. For example, highly integrated, host-beneficial endosymbionts typically have extremely reduced genomes and metabolisms. However, we do not yet fully understand the specific mechanisms that drive this integration or if there is a specific order in which these changes must occur. To investigate the early stages of endosymbiont genome reduction, we greatly expanded available whole genome data for the nitrogen-fixing endosymbionts (spheroid bodies, SBs) of diatoms in the family Rhopalodiaceae. We used these data to reconstruct SB evolutionary history and to characterize SB core metabolic capacity. We found two key genes missing from all SB genomes, mltA and dnaA, which could provide points of host control over SB cell division. Although most of the SB core genome is experiencing moderately strong purifying selection, we identified 54 genes under positive selection. Eighteen of these are peripheral proteins or involved in cell wall and cell membrane metabolism and could be involved in direct interactions with the host. Unexpectedly, we also found three nif genes under positive selection that are core to the central nitrogen-fixing enzyme. Overall, our results provide early insights into how SBs and their hosts interact, showing that SBs are still in the early stages of endosymbiont genome reduction, but they differ in key ways from current models, including the early loss of all mobile elements.

evolutionary biology↗

bioRxiv2026

ChironRNA: Steric Clashes Resolution in RNA Structures via E(3)-Equivariant Diffusion

Due to the limited resolution of experimental data, many determined RNA structures contain physically implausible geometries, such as severe steric clashes and missing atoms. Resolving these defects during RNA structure refinement remains a fundamental challenge. Structure dictates the function, so the geometric accuracy of RNA structure is critical for understanding biological mechanisms. However, traditional algorithms for correction have limitations because of the complexity of RNA structures. We propose ChironRNA, an all-atom diffusion model with E(3)-equivariant graph neural networks to perform RNA refinement by resolving steric clashes and completing missing atoms. In ChironRNA, we adopt a hierarchical approach, including both an all-atom diffusion model and a coarse-grained diffusion model where each nucleotide is represented by a five-point representation. Our pipeline consists of two stages: a training stage and a generation stage. The diffusion model regenerates clashing nucleotide atoms step by step by removing the noise predicted by EGNN. ChironRNA achieves an 80% clash reduction on more than 80% of the test set. It performs better on structures of less than 200 nucleotides, resulting in a high percentage of cases having over 80% clash reduction rate and 100% atom reconstruction rate. Our results demonstrate that ChironRNA successfully resolves steric clashes and rebuilds missing atoms with high precision, offering a robust solution where traditional fine-tuning or enumerative approaches fail.

biophysics↗

bioRxiv2026

In vivo multiomic Perturb-seq with enhanced nuclear gRNA capture

In vivo CRISPR screening with joint transcriptomic and chromatin readouts has been limited by inefficient recovery of gRNAs from nuclei. Here, we developed in vivo multiomic Perturb-seq, an effective platform combining nuclear transcript anchoring with gRNA-specific capture and amplification to enable high-fidelity, high-recovery gRNA assignment and scalable perturbation-resolved single-nucleus multiomics. Applying this platform to interrogate neurodevelopmental disorder risk genes in the developing cortex reveals cell-type-specific transcriptomic and epigenomic perturbation phenotypes.

genomics↗

bioRxiv2026

Indazolone-Based Molecular Glue Degraders as a Tunable Platform for Reprogramming Cereblon Substrate Specificity

Molecular glue degraders (MGDs) represent a transformative modality in drug discovery, with the cereblon (CRBN)-MGD axis offering a strategic gateway to systematically address the historically undruggable proteome. However, the limited chemical diversity of existing CRBN-mediated MGDs has constrained the full exploration of the degradable landscape. Here, we introduce an innovative indazolone-based platform that extends beyond canonical isoindolinone-glutarimide scaffolds, significantly expanding the accessible chemical space for CRBN modulation. Guided by mechanistic insights into CRBN-MGD complex conformational plasticity, we rationally designed indazolone architectures as novel CRBN ligands, developing diverse MGDs with potent ligase binding and exceptional substrate programmability. This platform enables fine-tuned control over neo-substrate recognition, supporting diverse degradation profiles ranging from the broad targeting of critical proteins (IKZF1/3, ZFP91, and LIMD1) to the exquisitely selective degradation of CK1 and IKZF2. Beyond expanding the chemical landscape for intractable targets, our indazolone-based MGDs exhibit favorable pharmacokinetic properties, offering robust promise for therapeutic development. Collectively, the remarkable tunability and exceptional neo-substrate programmability of the indazolone-based platform provide a highly transformative blueprint for next-generation MGD discovery, enabling systematic exploration of the vast CRBN-accessible proteome. Furthermore, as superior CRBN ligands, this platform holds immense potential for PROTAC discovery to systematically address previously intractable targets.

biochemistry↗

bioRxiv2026

Comprehensive long-read transcriptome analysis uncovers alternative RNA processing feature and isoform diversity in ovarian cancer progression

Post-transcriptional processing has a crucial yet largely unresolved dynamic change and role during the malignant progression of ovarian cancer, especially due to the limited read length of short-read RNA sequencing being insufficient to capture transcript diversity. Here, we performed Iso and RNA sequencing on paired normal, primary tumor, and metastatic samples, generating a comprehensive isoform atlas of over 41,000 full-length transcripts including many unannotated isoforms. Integrative analyses revealed extensive isoform-level remodeling across disease states that often occurred without concordant alterations at the gene level, emphasizing the importance of qualitative transcript regulation. Notably, we identified isoform-level alterations with distinct biological and clinical relevance, including differential expression of the short KRAS isoform, a tumor-specific isoform switch of TMEM201, and an alternative first-exon event in FNDC3B associated with poor survival. Together, these findings provide a high-resolution map of the ovarian cancer transcriptome and illustrate how long-read sequencing exposes multiple layers of post-transcriptional and clinical insight that remain hidden in conventional expression profiling.

bioinformatics↗

bioRxiv2026

Ubiquitination-mediated mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy

Seedling emergence is a pivotal step of plant survival, requiring rapid hypocotyl elongation for soil penetration. This energy-demanding process necessitates active mitochondrial respiration, which inevitably induces oxidative damage. Therefore, plants evolved a quality control mechanism that selectively removes dysfunctional mitochondria through the mitophagy pathway. Here, we identified SPL2, a mitochondrial E3 ligase which is essential for hypocotyl elongation and seedling emergence through degrading mitochondrial outer membrane proteins, such as TRB1 and FIS1A. Intriguingly, these proteins also interact with an ER protein, VAP27-1, forming a complex at the ER-mitochondria contact sites, which is essential for mitophagy initiation. The spl2 mutant exhibits enhanced ER-mitochondrial tethering and mitophagy activation, whereas its overexpression has the opposite effects. The expression of SPL2 increases after light perception, in agreement with the reduced mitophagy. Collectively, our findings reveal novel mechanistic insights into seedling emergence, which are coordinated through protein ubiquitination, ER-mitochondrial interaction, and mitophagy.

plant biology↗

bioRxiv2026

Antarctic marine microplastics reveals environmental persistence and rapid evolution of Candida auris

Candida (Candidozyma) auris is a critical priority fungal pathogen that emerged two decades ago near simultaneously on multiple continents. Since emergence, C. auris resistance to all four classes of antifungal drugs has been described, including pan-drug resistant isolates, sometimes evolving within patients. Here, we confirm the first isolation of C. auris from Antarctica and show cold-adapted phenotypes and an affinity for binding to nylon. We also provide evidence to suggest mutator phenotypes contribute to the rapid evolution of C. auris and are responsible for the emergence of multiple, distinct genetic clades worldwide. Isolates in clades I, III and IV with a mutator phenotype displayed elevated mutation rates compared to non-auris Candida species. This phenotype had a complex genetic basis and was associated with drug resistance mutations. We postulate that the mutator phenotype has a significant effect on evolutionary potential and is responsible for the emergence and rapid spread of drug-resistance C. auris and novel genetic clades.

microbiology↗

bioRxiv2026

Instantaneous Beta Frequency Regulates Self-Generated Timing in Humans

Self-generated timing requires the brain to determine when to terminate an ongoing action without reference to external cues. Although beta-band oscillations have been implicated in temporal control, how their intrinsic dynamics shape moment-to-moment variability in internally generated time remains unclear. Here, combining scalp EEG with intracranial recordings in humans, we show that the instantaneous frequency of beta oscillations (13-30 Hz) provides a dynamic control signal for self-generated timing. During a self-paced time production task, higher instantaneous beta frequency reliably predicted longer produced durations, both within individuals on a trial-by-trial basis and across individuals. This relationship was beta-specific, frontoparietally distributed, robust to motor and spectral confounds, and validated by convergent intracranial recordings. These findings run counter to classical pacemaker-accumulator models and instead establish beta-frequency dynamics as a mechanism that delays action termination by increasing the density of intrinsic stabilizing control updates during self-generated timing.

neuroscience↗

bioRxiv2026

Electrophysiologically Targeted Biopsies Reveal the Transcriptional Landscape of Focal Epilepsy

Up to 30% of patients with epilepsy have intractable seizures, yet the mechanisms of focal ictogenesis remain unclear. Tissue involvement in ictal regions is heterogeneous, with different regions playing distinct roles in ictogenesis, seizure propagation, and resistance to spread. These roles are reflected in electrophysiologic differences between the seizure focus and the ictal penumbra, where evidence of synaptic spread is present but excitatory firing is constrained by largely intact inhibition. Investigation of the disruption of the normal interplay between excitatory and inhibitory activity, thought to underlie ictogenesis across a range of epilepsy etiologies, is limited by network complexity and cellular heterogeneity in human tissue samples. In this study, we relate cellular and molecular alterations to excitatory-inhibitory disruption in network dynamics defined by electrophysiologic features. This work may aid in the identification of clinically relevant tissue biomarkers and support novel preclinical therapeutic approaches for treatment-resistant focal epilepsy disorders. We developed a novel intracranial EEG guided, MRI-localized approach to sample paired biopsies from 11 patients with drug-resistant focal epilepsy with diverse etiologies, which were then studied using single-nucleus RNA sequencing (snRNAseq) and immunohistochemistry (IHC). EEG recorded from stereotactically implanted depth arrays (sEEG) was used to identify regions of epileptic involvement, based on findings from prior simultaneous clinical and microelectrode recordings. This approach addresses the intrinsic heterogeneity due to etiology and cortical architecture through paired, within-patient comparisons. We identified distinct cell-type specific transcriptional signatures that differentiate cellular populations in the seizure focus and ictal penumbra in intractable focal epilepsies. Our findings provide a link between tissue composition and gene expression that correlate with electrographic features in a heterogeneous seizure landscape. Our findings support common pathways of seizure generation and spread that are conserved across disease etiologies. Relative depletion of interneuron populations in the seizure focus supports the hypothesis of disrupted inhibition as a driver of epileptiform activity in the seizure focus. The enrichment of plasticity-associated gene signatures in the penumbra suggests a complex interaction of these regions with the seizure focus, as well as the role of the penumbra in enabling or limiting seizure expansion. This study provides a novel methodology for tissue sampling in epilepsy and uncovers biologically relevant tissue signatures that provide grounds for future work in targeting cellular and molecular alterations present in focal epilepsies.

neuroscience↗

bioRxiv2026

Multi-omic profiling of human and mouse dorsal root ganglia enables targeted gene delivery to nociceptors

Chronic pain conditions are often driven by hyperexcitability of nociceptors, the peripheral sensory neurons that detect noxious stimuli. Recent single-cell transcriptomic studies have begun to clarify the molecular identity of distinct peripheral sensory neuron subtypes, but tools that restrict transgene expression to nociceptors while sparing other dorsal root ganglion (DRG) subtypes remain limited. Here, we combined single-nucleus multi-omic profiling of human and mouse DRG with in vivo AAV enhancer screening to identify cis-regulatory elements that drive biased AAV expression in mouse DRG nociceptors and human iPSC-derived nociceptors. We then validated that an enhancer AAV designed to express Kir2.1 preferentially in nociceptors reduces DRG neuronal excitability. Leveraging these multi-omic datasets, we trained a sequence-based model to decode the cis-regulatory logic of nociceptors, enabling both the prioritization of native candidate elements and the design of synthetic enhancers with a range of nociceptor targeting properties. Together, these cross-species multi-omic resources define conserved DRG regulatory programs and provide a viral toolkit for pain research with potential translational applications for patients with refractory pain.

neuroscience↗