Biology subjects

Jiang, H.

Publications and source records attributed to Jiang, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Bispecific T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T-cells

Bispecific T cell engagers (TCEs) often exhibit limited efficacy in solid tumors, in part due to immunosuppressive cues in the tumor microenvironment and low expression of targetable tumor antigens. Therapeutic strategies to improve TCE target sensitivity and enhance T cell effector functions therefore have significant translational potential. Here, we engineered TCEs that induce T cell activation in vitro against the low-abundance target antigens, TRP2/Kb and DLL3. Despite in vitro activity in these models, TCE monotherapy showed limited control of tumor growth in immunocompetent mice. Leveraging this in vivo model of TCE treatment failure, we discovered that co-treatment with TCE and a CD25-biased Interleukin-2 (IL2) rescues anti-tumor activity. Further, multimodal single-cell transcriptomic and immune repertoire analyses revealed that TCE-IL2 combination therapy controlled tumors by recruiting and activating new CD8+ T cells into the tumor microenvironment. These findings demonstrate that TCE-mediated anti-tumor responses function through a CD8+ T cell clonal replacement mechanism that can be augmented by cytokine therapy. One Sentence SummaryCombining TCE therapy with IL-2 enhances TCE efficacy in aggressive small-cell lung cancer and melanoma models with low target antigen density through T cell clonal replacement and CD8+ effector T cell differentiation.

cancer biology↗

bioRxiv2025

An ancient transcription factor functions as the master regulator of primary cilia formation

How ancient transcription factors are repurposed during evolution to drive the functional diversification of conserved organelles remains a fundamental question in biology. Although highly conserved in basic morphology, eukaryotic cilia vary extensively in their sizes and functions. Previously, we showed that an evolutionarily ancient transcription factor, X chromosome-associated protein 5 (Xap5), controls motile ciliogenic transcriptional programs during mouse spermatogenesis (Wang et al., 2025). Here we show that Xap5 functions as the master regulator of primary ciliogenesis. Xap5 associates with the nuclear protein Non-POU domain-containing octamer-binding protein (Nono) to form a regulatory module that directly binds and activates the transcription factors Sox5 and Sox9. Genetic ablation of Xap5 or Nono impairs primary ciliogenesis, and loss of Sox5 disrupts the downstream ciliogenic program, consistent with the established role of Sox9. Collectively, our results provide new insight into how complex ciliary transcription factor networks determine ciliary diversity during evolution, and suggest that defects in this regulatory axis may contribute to the etiology of human ciliopathies.

cell biology↗

bioRxiv2025

Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCs

Low-affinity transcription factor (TF) motifs are an important element of the cis-regulatory code, yet they are notoriously difficult to map and mechanistically incompletely understood, limiting our ability to interpret non-coding variation in development, evolution, and disease. Here we investigate their role in pioneering and leverage sequence-to-profile models of chromatin accessibility in mouse embryonic stem cells to reliably map and interpret low-affinity motifs across the genome. We find that low-affinity motifs have outsized effects by cooperating with nearby motifs through intra-nucleosomal soft syntax. By modeling nucleosome-mediated cooperativity with a kinetic model, we discover and validate that pioneer cooperativity makes a motif operate at higher pioneering ranges across changing TF concentrations, thereby raising the regulatory potential. These results show that low-affinity motifs can be accurately mapped, shape the properties of developmental enhancers and likely play a widespread role in fine-tuning enhancers during evolution.

genomics↗

bioRxiv2025

Multimodal AI Decodes Extreme Environment Functional Dark Matter Beyond Homology

Functional annotation of proteins from extreme environments represents a major bottleneck for bioresource discovery, as a vast reservoir of functional dark matter defies existing homology-based methods. We demonstrate that environmental pressures impart conserved physicochemical energy signatures that co-determine protein function with sequence and structure. Here we developed ACCESS, a multimodal graph neural network employing hierarchical contrastive learning with a tailored label-sample co-embedding to fuse energy, sequence, and structural information and overcome homology scarcity. ACCESS surpasses state-of-the-art methods including BLASTp and CLEAN in annotating low-identity enzymes. Applied to extreme environmental metagenomics, we constructed a function map of extremophile enzymes to expand the biocatalyst library, pinpointed functionally critical residues to guide rational design, and enabled large-scale, function-based macro-evolutionary analyses. This paradigm transcends the limitations of homology, illuminating protein dark matter and accelerating the exploration of the biospheres functional diversity for applications in biotechnology and therapeutic development.

bioinformatics↗

bioRxiv2025

Cross-task, explainable, and real-time decoding of human emotion states by integrating grey and white matter intracranial neural activity

Decoding human emotion states from intracranial neural activity is key in developing brain-computer interfaces and new therapies for affective disorders. However, real-world application of decoding requires high performance that integrates neural activity from both grey and white matter, stable generalization across different contexts, sufficient neural encoding explainability, and robust real-time implementation, all of which remain elusive. Here, we simultaneously recorded intracranial electroencephalogram (iEEG) and abundant self-rated valence and arousal scores across two emotion-eliciting tasks in eighteen subjects, forming the largest intracranial neural dataset for emotion decoding. We then developed personalized decoding models within a hybrid deep learning framework involving both self-supervised and supervised components. The models achieved high-performance decoding of continuous valence/arousal states, doubling the R-squared performance of prior EEG/iEEG decoding. Critically, the models significantly improved performance by integrating grey and white matter signals and demonstrated cross-task generalization. The models further revealed shared and preferred mesolimbic-thalamo-cortical subnetworks encoding valence and arousal, showing neurophysiological explainability. Finally, the models realized robust real-time decoding in four new subjects. Our results have implications for advancing emotion decoding neurotechnology toward deployable affective brain-computer interfaces and closed-loop therapeutic systems for affective disorders.

neuroscience↗

bioRxiv2025

Na+/H+ Exchanger Isoform 1 Regulates Apoptosis Susceptibility in Pulmonary Arterial Smooth Muscle from the Sugen/Hypoxia model of Pulmonary Hypertension

Pulmonary hypertension (PH) is characterized by vascular remodeling driven in part by apoptosis-resistant pulmonary arterial smooth muscle cells (PASMCs). Na/H exchanger isoform 1 (NHE1) regulates intracellular pH and plasma membrane cytoskeleton anchoring, influencing PASMC migration and proliferation, but the role of NHE1 in apoptosis remains unclear. NHE activity and NHE1 surface expression were increased in PASMCs from the Sugen/Hypoxia (SuHx) rat model compared to controls. Despite increased endoplasmic reticulum (ER) stress at baseline, SuHx PASMCs were resistant to apoptosis following H2O2 challenge. Pharmacological inhibition of NHE activity with ethyl-isopropyl amiloride (EIPA) and silencing with siRNA restored apoptosis in SuHx PASMCs. Conversely, NHE1 overexpression in control PASMCs conferred apoptosis resistance. Expression of mutant NHE1 constructs lacking ion translocation or binding to the adaptor protein, ezrin, also reduced H2O2-induced apoptosis. Mechanistically, apoptotic stimulation with H2O2 increased p38 phosphorylation in PASMCs from control, but not SuHx, rats, indicating impaired activation of this pro-apoptotic pathway. NHE1 suppression via EIPA or siRNA restored p38 phosphorylation in SuHx PASMCs, while overexpression of NHE1 (wild-type or mutants) suppressed p38 activation following apoptotic stimulation. Inhibition of p38 with SB203580 prevented the pro-apoptotic effect of EIPA, validating a role for p38 signaling in NHE1-mediated apoptosis resistance in SuHx PASMCs. These findings identify NHE1 as necessary and sufficient for PASMC apoptosis resistance in PH, by a mechanism independent of ion transport or ezrin-binding functions but involving suppression of p38 phosphorylation. Targeting NHE1-dependent pathways may restore PASMC apoptosis and offer a novel therapeutic strategy to reverse pulmonary vascular remodeling in PH.

physiology↗

bioRxiv2025

A sensory system for mating in octopus

Sensory systems for mate recognition maintain species boundaries and influence diversification. Therefore, uncovering how molecules and receptors evolve to mediate this critical function is essential to understanding biodiversity. Male octopuses use a specialized arm called the hectocotylus to identify females and navigate their internal organs to reach the oviduct and deliver sperm. Here, we discovered that the hectocotylus is a dual sensory and mating organ that uses contactdependent chemosensation of progesterone, a conserved ovarian hormone. We identify chemotactile receptors for progesterone and resolve the structural basis for their evolution from ancestral neurotransmitter receptors and subsequent expansion and tuning across cephalopods. These findings reveal principles by which sensory innovations shape reproductive behavior and suggest mechanisms for how sensory evolution contributes to the diversification of life.

cell biology↗

bioRxiv2025

Force loading on molecular clutches governs the stability of cell lamellipodia

Cells can utilize the lamellipodia, a thin actin-rich membrane protrusion, to probe the mechanical properties of microenvironments. During the mechanosensing process, the lamellipodium usually exhibits instability in dynamics, i.e., protrusion-retraction cycles. However, how mechanical instability arises in lamellipodia, along with the functional role of dynamic instability in mechanosensing, is poorly understood. Here, we develop a minimal mechanochemical model for lamellipodia dynamics that integrates membrane deformation, myosin contractility, and binding kinetics of adhesion molecules (molecular clutches). Through stochastic simulations and analytical mean-field analysis, we demonstrate that both force-loading rate and magnitude applied by myosin-driven retrograde flow mediate the clutch binding kinetics, governing lamellipodial stability and hence the mechanosensing. Specifically, a slow force loading rate allows the clutches to bind and traction to accumulate, while a high loading magnitude collapses the bound clutches, causing protrusion-retraction cycles (instability) in lamellipodia. Our model predicts that a stiffer substrate stabilizes the lamellipodia by increasing the force loading rate, consistence with previous experiments. Furthermore, our model predictions on the biphasic regulation effect of myosin perturbations have been quantitatively validated by experimental results. Overall, the theoretical framework highlights the force loading as the key mechanical input driving lamellipodial instability and cell mechanosensing, advancing our understanding of mechanotransductions role in cell behaviors. SignificanceCell behavior can be highly dynamic, showing periodic protrusion and retraction at the leading edge, and this dynamic instability is key to migration, immune response, and cancer invasion. How such instability arises from mechanotransduction between intercellular components and extracellular matrices remains unclear. Here, through theoretical modeling, we identify the rate and magnitude of force loading on adhesion molecules (molecular clutches) as the key factors for controlling lamellipodial stability. We find that a slow loading rate enables more clutches to bind and traction to accumulate, while a high loading magnitude collapses the bound clutches, causing protrusion-retraction cycles in lamellipodia. This work reveals a physical mechanism of how cells sense mechanical cues and adapt their dynamics, offering insights into diverse biological processes.

biophysics↗

bioRxiv2025

A Micro-Engineered Heart Tissue Model of Desmin-related Cardiomyopathy Caused by Mutant αB Crystalin

Protein quality control (PQC) is essential for maintaining sarcomere integrity in cardiomyocytes. Crystallin B chain (CRYAB) R120G mutation disrupts CRYABs chaperone activity, leading to aggregation of CRYAB and its client proteins (including Desmin), leading to Desmin-related cardiomyopathy (DRM). Prior experimental systems for modeling DRM linked to CRYAB require massive overexpression of CRYAB mutant isoforms, raising questions about translational relevance. Here, we establish the first model of CRYAB-linked DRM that uses genome-edited hiPSC together with isogenic controls, allowing us to study the impact of mutant CRYAB expressed at near endogenous levels. Within micro-engineered heart tissues (HT), CRYAB-R120G mutant hiPSC-derived cardiomyocytes recapitulated key DRM hallmarks, including Desmin and CRYAB aggregation, contractile dysfunction, and increased vulnerability to PQC pathway inhibition. CRYAB-R120G mutant HT also exhibited dysfunctional calcium-contraction coupling, which exacerbated contractile deficits at higher pacing frequencies. JAK1 inhibition with Itacitinib partially restored contractile function at higher pacing frequencies, suggesting JAK1 inhibition as a viable therapeutic strategy. By preserving human-specific structural and functional features, our {micro}HT platform enables mechanistic characterization of proteotoxic cardiomyopathies and offers a scalable system for targeted drug screening.

bioengineering↗

bioRxiv2025

Autonomous liquid-handling robotics scripting through large language models enables accessible and safe protein engineering workflows

Laboratory automation accelerates synthetic biology, but robot programming remains a barrier to broader participation. Large language model (LLM)-based automation must address four interconnected requirements in this field: sequence-level biosecurity, community standards, context-dependent biological behavior, and distributed collaboration across laboratories. Here we present LabscriptAI, an execution-aware agent framework that couples authoring and runtime control loops to translate natural-language instructions into platform-specific robot scripts and support bounded recovery under deterministic authorization and human oversight. On a 90-task liquid-handling benchmark, LabscriptAI achieved a 96.7% simulation-pass rate, the highest among the evaluated LLM-based and commercial baselines. We demonstrated its capabilities through sequence screening at designated workflow checkpoints; standardized cell-free characterization of 854 green fluorescent protein (GFP) designs from 171 student teams, coupled to data deposition; containment-aware engineering of a formaldehyde-converting enzyme, yielding 6.7-fold higher ethylene glycol titers in a two-stage cascade; and quality-assured preparation of 531 genetic parts for the 2025 iGEM Distribution Kit distributed worldwide. Together, these results establish LabscriptAI as a biosecurity-aware, community-integrated framework connecting protocol authoring, controlled execution, and traceable experimental outputs across laboratory platforms.

bioengineering↗

bioRxiv2025

Structural insights into a conserved mechanism of choline translocation through CHT

The essential nutrient choline is critical for cellular homeostasis across all domains of life. In humans, choline uptake in cholinergic neurons for its recycling into acetylcholine is mediated by the high-affinity Na-dependent transporter SLC5A7 (also known as CHT1). Prokaryotes also depend on choline as an osmo-protectant and as metabolite, raising the possibility that bacteria also possess choline transporters akin to CHT1. Here, we present a bacterial Na+-dependent choline transporter (sfCHT) with high sequence identity to CHT1. sfCHT transport activity can be blocked by the choline transport inhibitor hemicholinium-3. Cryo-EM structures of Na+- and choline-bound sfCHT reveal a 14 transmembrane helix topology with a LeuT-fold architecture and Na+ coordination geometry similar to CHT1. Captured in an inward-facing conformation, in sfCHT choline is found at a site near the cytoplasmic side. Computational analysis and transport assays reveal local conformational changes along a choline translocation pathway to the cytosolic site. Transport assays with CHT1 variants, carrying substitutions at conserved residues along the proposed translocation pathway in sfCHT, reveal a conserved mechanism of choline transport between the bacterial and human choline transporters.

biophysics↗

bioRxiv2025

The serine protease homolog Skanda modulates Toll-Phenoloxidase-mediated immunity in Drosophila

Extracellular serine protease (SP) cascades are central regulators of insect innate immunity. These cascades are negatively controlled by serine protease inhibitors (serpins) and fine-tuned by serine protease homologs (SPHs), which resemble SPs but lack catalytic activity. In Drosophila, a key SP cascade--the Toll-phenoloxidase (PO) pathway--governs both the melanization response and Toll-dependent antimicrobial peptide production. This cascade is triggered by secreted pattern-recognition receptors or microbial proteases and converges on two clip-domain SPs, Persephone and Hayan, which activate the Toll ligand Spatzle via the Spatzle-Processing Enzyme (SPE) and process prophenoloxidases. Here, we characterize the SPH Skanda and uncover its role in the Toll-PO cascade. skanda is genomically clustered with hayan and persephone and is transcriptionally induced upon infection. Skanda is unusual among SPHs, containing a long serine/threonine-rich region, two clip domains, and atypical disulfide bonds. Skanda is unstable and subject to cleavage by Grass. Functional assays show that Skanda dampens activation of Hayan, and to a lesser extent Persephone, within the Toll-PO cascade. Notably, skanda-deficient flies are highly susceptible to Staphylococcus aureus despite displaying normal Toll signaling and cuticular melanization. Moreover, compound mutants lacking two members of the hayan-psh-skanda cluster reveal a hidden contribution of Skanda to Toll activation in the absence of Persephone. Together, our results identify Skanda as a modulatory SPH that fine-tunes Toll pathway activity in concert with Persephone and Hayan.

immunology↗

bioRxiv2025

Cortex-Wide Substrates for Body Schema and Action Awareness

The concept of the body schema originated from studies of patients with cortical lesions who were unable to localize their body parts in space or perceive passive movements (Head & Holmes, 1911). Current consensus defines the body schema as the brains internal representation of the body configuration in space used for both embodied perception and voluntary action (de Vignemont, 2010; Berlucchi & Aglioti, 2010; Vallar et al., 2025). Despite extensive research, how the cortex efficiently encodes the vast repertoire of body postures to support natural behavior remains poorly understood. Here, we reveal the representational format underlying the body schema by combining large-scale electrophysiological recordings with full-body 3D tracking and joint angle computation in freely behaving mice. Across cortical regions, neurons encoded diverse postural features in distinct reference frames: posterior parietal cortex (PPC) populations preferentially encoded body midline-referenced features, while sensorimotor cortices utilized a gravity-referenced frame. Strikingly, during performance of different stereotyped actions, distinct cortical ensembles were selectively activated. These action ensembles fired in phase-locked sequences that tiled the full action cycle, providing a neural substrate for action awareness. A network model recapitulated these dynamics and identified low-dimensional action subspaces within population activity. Together, these findings reveal that the cortex organizes the body schema around actions, compressing high-dimensional kinematics into an efficient, body-midline-and gravity-anchored, action-aware neural code.

neuroscience↗

bioRxiv2025

Metabolic Immunosuppression Mediated by Proliferative CD168+TAMs in Colon Cancer

The role of non-monocyte-derived, in situ proliferating tumor associated macrophages (TAMs) in tumor progression has been underappreciated. Proliferative TAM subsets likely represent critical mediators in establishing the immunosuppressive microenvironment, given the susceptibility of TAMs to be hijacked by malignant cells for pro-tumorigenic functions. However, the regulatory networks governing their self-renewal circuitry and lineage bifurcation remained undefined. Combining single cell RNA sequencing of human and murine colon tumors, we identified CD168+ TAMs, a hyperproliferative subpopulation with FOXM1-dependent maintenance of replicative competence. Spatial multi-omics and functional validation revealed that this subset exhibited peritumoral localization and underwent immunosuppressive polarization through cholesterol-coordinated CX3CL1-CX3CR1 signaling. Colon cancer-specific lipid metabolic rewiring elevates glycerophospholipid and cholesterol flux, with PLA2G7-mediated glycerophospholipid catabolism promoting CX3CR1 expression in TAMs. Thus, the CX3CR1 signaling-driven immunosuppressive effect of CD168+ TAM is an integrated response to tumor-specific metabolic features. Targeting the CD168+ TAMs may enable therapeutic strategies for metabolic-immune reshaping in colon cancers.

cancer biology↗

bioRxiv2025

Disgust propensity, not disgust sensitivity, shapes the reactivity of a subjective disgust circuit in humans

Disgust constitutes an evolutionary adaptive defensive-avoidance response, yet humans vary markedly in their dispositional tendency to experience disgust (disgust propensity) and in their negative appraisal of such experience (disgust sensitivity). Conceptual frameworks and neuroimaging studies suggest that these traits may differentially modulate neural responses to disgust-eliciting stimuli; however, methodological constraints have left their precise roles unresolved. Our comparably large fMRI study (n = 142) therefore aimed to systematically determine how trait disgust modulates neural responses to carefully selected and validated disgust-specific visual stimuli across varying levels of subjective disgust experience. The whole-brain voxel-wise regression analyses revealed a neural dissociation between the two disgust traits, with disgust propensity, but not disgust sensitivity, modulating disgust-related neural activity in the anterior, middle, and posterior insula, as well as the caudate, putamen, thalamus, hippocampus, and parahippocampal gyrus. Mediation and network-level analyses further supported this dissociation by showing that disgust propensity shapes disgust experience via insula - striatal - hippocampal pathways. Together, these findings provide evidence for a neurofunctional dissociation of disgust propensity and sensitivity and elucidate how trait disgust shapes subjective experiences. They further suggest that disgust propensity and the identified systems may represent promising targets for the regulation of disgust-related pathology.

neuroscience↗

bioRxiv2025

Divergence of Bowman-Birk Protease Inhibitor Family into seed-specific and environmentally responsive subfamilies in Legume and Soybean: Implication for Legume Seed Composition Improvement.

Bowman-Birk inhibitors (BBI) are an ancient class of serine protease inhibitors originating prior to the emergence of the angiosperms. While BBIs have been preserved in the legume (Fabaceae) and cereal (Poaceae) families, they have been lost in many other divergent lineages. However, their underlying molecular evolution and regulation of BBI remain largely uncharacterized. Our study shows that BBIs in legumes and cereals are encoded by two large and divergent gene families. BBI genes in legumes have further diversified into two subfamilies with distinct gene expression patterns. Genes in one legume BBI subfamily are specifically expressed in seeds while BBI genes in the other legume subfamily and cereal do not have significant expressions in any examined tissues including seed, root, leaf and flower. The soybean BBI gene family shows evidence of expansion via whole genome, segmental and tandem duplication. Protein sequence and structural analysis predicts that functional domains for double-headed inhibitory loops and binding abilities to trypsin and chymotrypsin are largely preserved within the soybean BBI family. The seed-specific subfamily genes are specifically expressed at maturation stages and not at embryogenesis stages. The other, non-seed BBI subfamily genes are highly responsive to a distinct spectrum of signals related to abiotic and biotic stresses. Their specific expression under non-essential biological processes for plant growth and development suggests that, although BBIs have been retained in both cereals and legumes, likely due to their role in enhancing plant fitness under natural selection pressures, they are not involved in core developmental processes. This may explain why BBIs were lost in many divergent plant lineages and support their well-established roles in plant adaptation to environmental stress. Having knocked out the seed-specific BBIs through a CRISPR/Cas9 approach, we have successfully generated soybeans which exhibited 69.4 - 73.7% reduction of trypsin inhibitor activity and 76.4 - 79.4% reduced chymotrypsin inhibitor activity. The edited soybean did not show significant changes in key agronomic traits, supporting that the functions of BBIs are not essential. While BBIs in soybean seeds may have a desirable function in natural selection, they are antinutrients from an applied perspective for their use in feed and food. It provides an opportunity to reduce BBIs in seeds for quality improvement. Our findings provide insights into molecular evolution, regulation, and function of BBI in plants, and successfully demonstrate engineering BBI in seeds to result in production of food and feed of higher nutritional value with minimal impacts on the agronomic performance of the plant.

plant biology↗

bioRxiv2025

Core gastric microbiota linked to pathogenesis and preserved across age stratified cohorts

Mounting evidences reveal a complex microbial niche in gastric environment. Nevertheless, the phylogenetic stability of gastric microbiota remains undetermined. Here, using full-length 16S rRNA and ITS amplicon sequencing applied to gastric brushes from a pediatric endoscopic cohort (n=243), we identified a core microbiota comprising 11 genera, which clustered into two antagonistic communities (CST1A and CST1B). CST1A was enriched in healthy subjects, while CST1B correlated with gastroduodenal disease. Notably, this bipartite architecture arose through bacterial interactions, with fungal taxa demonstrating minimal integration. Further stratified analyses revealed that H. pylori infection preferentially depleted CST1A taxa. The subclusters exhibited divergent metabolic profiles, with CST1A specializing in motility processes and CST1B in nucleotide/peptidoglycan synthesis. Cross-cohort validation of six datasets (n=1,183) confirmed the persistent relevance of the CST1A-CST1B structure across disease stages. Collectively, our findings define a core gastric microbiota established in early life, linked to gastric disease risk, and persisting into adulthood. HighlightsO_LIIdentification of a gastric bacterial network established in early life. C_LIO_LIDysbiosis in two subclusters within the core microbiota is associated with pediatric peptic ulcers. C_LIO_LIHelicobacter pylori infection reduces the abundance of the core microbiota, with a particularly greater inhibitory effect on CST1A. C_LIO_LIThe core microbiota is preserved across age stratified cohorts and is associated with gastric cancer. C_LI

microbiology↗

bioRxiv2025

An integrated multi-tissue atlas of epigenomic landscapes and regulatory elements in the bovine genome

Deciphering the regulatory syntax of the genome is essential to understand the genetic and molecular architecture of complex traits, as most trait-associated variants lie in non-coding regions. Yet, functional annotation of the bovine genome remains limited, hindering our ability to unravel the mechanisms underpinning complex traits of economic and ecological importance in cattle. Here, we present a comprehensive epigenetic atlas comprising 1,138 genome-wide epigenetic profiles, including chromatin accessibility, six histone modifications, CCCTC-binding factor (CTCF) transcription factor binding, DNA methylation, chromatin conformation, and transcriptomes across 53 adult tissues, five fetal tissues, and seven primary cell types. This atlas-level data enables us to annotate around 45% of the genome as putative regulatory elements exhibiting tissue- or cell-specific regulatory activity. Leveraging sequence-to-function deep learning models, we discovered 301 sequence motifs and predicted the functional impact of genetic variants through in silico mutagenesis, thereby facilitating the decoding of the regulatory syntax of the cattle genome and fine-mapping of GWAS loci for 22 complex traits. Cross-species analysis further revealed evolutionarily conserved features of regulatory architecture and provided evolutionary insights into complex traits and diseases in humans. Together, this atlas offers a foundational resource for advancing cattle functional genomics, sustainable breeding, and studies of regulatory evolution.

genomics↗