Biology subjects

Cheng, C.

Publications and source records attributed to Cheng, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Shared and distinct immunometabolic states link to divergent pathology in cutaneous mycobacterial infections

Cutaneous mycobacterial infections provide a common tissue setting in which related intracellular pathogens elicit distinct pathological responses, but the innate immune basis of this divergence remains incompletely understood. Here, we combined single-cell profiling from 33 individuals with histological and functional analyses, examining healthy skin and lesions from multibacillary leprosy (MB), paucibacillary leprosy (PB), cutaneous tuberculosis (CTB) and Mycobacterium marinum infection (Mari). All infections showed lower mononuclear phagocyte and higher natural killer (NK) cell proportions within the CD45 compartment, alongside shared and infection-associated dendritic cell, macrophage and NK cell programs. CTB and Mari displayed broader macrophage antimicrobial signatures, whereas MB showed lipid-associated programs and attenuated interferon-associated effector expression across multiple macrophage subsets. Reduced expression of fructose-1,6-bisphosphatase 1 (FBP1) was associated with the absence of Langhans giant cells in MB, and pharmacological FBP1 inhibition nearly abolished fusion of macrophages. Compared with NK cells from Mari, MB NK cells showed reduced central carbon and oxidative metabolism signatures alongside increased lipid-associated programs. Functional experiments showed that inhibition of glucose utilization, disruption of mitochondrial function, or co-culture with foamy macrophages abundant in MB lesions reduced NK cell IFN-{gamma} production. These findings identify shared and distinct innate immune programs and suggest that their interplay with local metabolic environments shapes divergent pathology across cutaneous mycobacterial infections.

immunology↗

bioRxiv2026

BiNVaST: niche boundary-preserving and synthetic data-guided variational autoencoders for concordant inference across high-resolution spatial transcriptomic platforms

High-resolution spatial transcriptomics (ST) enables subcellular spatially resolved transcript profiling but remains difficult to annotate in complex tissues because of gene coverage and super sparseness in expression. These challenges are amplified in cancer research, where neoplastic cell states and rare immune cells in tumor microenvironment are often poorly captured by generic references and/or cell typing tools exclusively built on molecular profile. Here, we present BiNVaST, a niche boundary-preserving and dual-branch variational autoencoder fused with statistical simulator for reliable cell typing across multiple spatial platforms. It generates platform-adjusted in silico training data by integrating query spatial profile and user-defined pre-annotated single-cell reference through Singular Value Decomposition and Optimal Transport, combining molecular similarity and spatial proximity to predict segmented cell labels. BiNVaST was benchmarked against existing methods across Xenium, CosMx, Stereo-seq, Visium HD platforms using six specimens from four tissue types. This tool is sensitive in detecting divergent tumor cell states and improves the cross-platform concordance, distinguishing disease-specific neoplastic and non-neoplastic cellular subpopulations and supporting robust cellular or niche inferences in heterogeneous tissues.

bioinformatics↗

bioRxiv2026

Characterization of the frameshift c.515dupC knock-in mouse model of HSPB8-associated myopathy (MFM13) and evaluation of Trehalose as autophagy modulating therapy.

Heat shock protein family B member 8 (HSPB8) is a chaperone involved in the chaperone-assisted selective autophagy (CASA) complex. HSPB8 in conjunction with cochaperone BAG3, promotes autophagy-mediated removal of misfolded proteins associated with various neurodegenerative diseases. Mutations in HSPB8, previously associated with Charcot Marie Tooth disease type 2L, have recently been linked to an autosomal dominant rimmed vacuolar myopathy (MFM13), and is considered a multisystem proteinopathy. Patients have distal and proximal limb girdle myopathy with muscle biopsy showing fatty replacement, endomysial fibrosis, and rimmed vacuoles leading to muscle atrophy and early demise. We have demonstrated reduced expression of HSPB8, altered autophagy and TDP-43 accumulation in patient fibroblasts. Using CRISPR technology, we generated a knock-in Hspb8 mouse model of the c.515dupC hot spot frameshift variant to study disease pathology. Overexpressed murine Hspb8 frameshift mutant (c.515dupC, fs) displays insolubility and aggregation propensity in Murine Neuroblastoma X Spinal Cord 34 (NSC-34) cells. Mutant Hspb8 mice developed late-onset muscle weakness beginning at 15 months. Muscle biochemical analyses revealed reduced HSPB8 levels, increased TDP-43, and altered autophagy markers, partially recapitulating the human phenotype. Fiber type analysis, neuromuscular junction integrity, and motor neurons show mild myopathy without neurodegeneration. Given the lack of available treatments, we evaluated trehalose, a natural disaccharide that induces HSPB8 and enhances autophagy. Administration of 2% trehalose in drinking water improves motor performance, restores HSPB8 expression, and ameliorates autophagic and TDP-43 pathology in mutant mice. These findings support the value of our preclinical models for translational studies, and autophagy enhancement as a potential therapeutic strategy for HSPB8-related myopathy.

genetics↗

bioRxiv2026

Recombination on 'non-recombining' sex chromosomes: empirical insights from the blackspotted stickleback

One hallmark of sex chromosome evolution is recombination suppression driven by inversions. The resulting non-recombining sex-linked regions accumulate deleterious mutations and functionally degenerate. The question therefore arises: why does selection not favor the reestablishment of recombination? Two (non-exclusive) explanations for this have been proposed: 1) selection to maintain linkage between the Primary Sex Determination Locus (PSDL) and sexually antagonistic loci - loci with alleles that are beneficial to one sex but detrimental to the other; and 2) the rarity of reversions - structural mutations that reverse the inversion that initially suppressed recombination. Empirical perspectives are sorely needed to evaluate the relevance of these models. Here, we characterised the intermediate stages of sex chromosome evolution in the blackspotted stickleback (Gasterosteus wheatlandi). We generated high-quality, phased assemblies and annotations for the X and Y chromosomes, as well as population-level sequencing. Using these data, we inferred distinct recombination loss events and their associated inversions. Most significantly, we find support from multiple lines of evidence for a [~]2 Mb recombination event that likely occurred via double crossover within an existing non-recombining inversion. This result highlights that rare recombination can occur within sex-linked inversions. Simulations suggest that such histories of gene flux may allow for a novel empirical framework, adapted from work on autosomal inversions, to infer evolutionary processes at work within sex-linked non-recombining regions and distinguish between models to explain the maintenance of recombination suppression on sex chromosomes. Significance StatementSex chromosomes have evolved countless times across eukaryotes and often lose the ability to recombine, causing them to degenerate over time. Why then, does recombination not restart to purge harmful mutations? By generating a high-quality genome assembly of the blackspotted stickleback, we discovered the strong empirical evidence of a sex chromosome undergoing a double-crossover event within a "non-recombining" region, which reset the degenerative process. This finding challenges the view that sex chromosome decay is a one-way street. Furthermore, using forward evolutionary simulations, we demonstrate that the genetic signatures left by such events could help identify the selective forces acting within non-recombining sex chromosomes, thereby explaining the maintenance of recombination suppression.

evolutionary biology↗

bioRxiv2026

Reliability-weighted target prioritization in CD4+ T-cell Perturb-seq: a generalizability-theory decomposition

Genome-scale Perturb-seq screens prioritize candidate targets by the strength of a perturbations transcriptional effect. Effect strength does not answer a prior measurement question: is the readout dependable? A large effect estimated from a single guide, a single donor, or a pseudobulk of few cells need not survive replication, and for target prioritization each false lead costs a validation experiment. We treat each perturbation effect as a measurement in a crossed Target x Guide x Donor x Condition design and apply generalizability theory (Brennan, 2001; Cronbach et al., 1972) to separate the dependable part of an effect from facet-specific idiosyncrasy. Guides and donors enter as random facets; condition enters as a fixed facet and is analyzed within its levels. For each target we report a dependability profile over the facets and a joint generalizability coefficient over the two random facets, and we re-rank targets by effect magnitude weighted by that coefficient. On the released screen (Zhu et al., 2025), removing the measurement-error floor estimated from the non-targeting controls raises the number of genes with a dependable target-signal share above .10 from 40 to 7,674. Analyzed within activation states, dependability recovers the T-cell-receptor signaling module as reliably measurable only in activated cells, without recourse to gene annotation. A design study indicates that reliability is limited by the number of guides rather than the number of donors, so a future screen should add guides. Every methodological decision was recorded and adversarially reviewed, and all results regenerate from the released summary statistics.

bioinformatics↗

bioRxiv2026

Targeting folate-dependent purine synthesis sensitizes melanoma cells to immune attack through suppressing glycolysis

Cytotoxic T lymphocytes (CTLs) play a central role in antitumor immunity; however, metabolic reprogramming within the tumor microenvironment often compromises their effector function, making metabolic targeting crucial for the improvement of T cell function. Folate-dependent purine synthesis, a core pathway sustaining the nucleotide pool, is highly activated in tumors, yet its role in regulating tumor immune sensitivity remains unclear. Here, by establishing a co-culture system of melanoma cells and human T Cell Receptor (TCR)-engineered T cells, we systematically evaluated the effects of folate-dependent purine synthesis inhibitors on tumor cell response to CD8+ T cell cytotoxicity. We found that inhibition of key enzymes such as methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and glycinamide ribonucleotide transformylase (GART) markedly enhanced tumor cell sensitivity to T cell killing, an effect also observed with exogenous nucleoside supplementation. Mechanistically, inhibition of folate-dependent purine synthesis suppresses glycolysis by downregulating critical glycolytic enzymes, thereby reducing lactate production. Reduction in lactate further weakens lactylation and stability of the immune checkpoint protein PD-L1. In parallel, impaired purine synthesis disrupts uridine metabolism, blocks ribose salvage, and distally influences glycolysis. Collectively, our study identified the folate-dependent purine synthesis - glycolysis axis as key regulator of tumor immune response and highlights metabolic targeting as a promising strategy to improve cancer immunotherapy.

cancer biology↗

bioRxiv2026

A Selective Multivalent NET-Associated Chromatin Neutralizer Resolves Infection-Associated Inflammation in Severe Sepsis

Targeting the overwhelming inflammation driven by neutrophil extracellular traps (NETs) during infection provides an opportunity to manage severe sepsis. This potential needs to be realized by exploring selective NET-neutralization materials, which remains a challenge. Herein, we report a multivalent macromolecular strategy that targets NET-associated DNA-histone chromatin complexes while preserving antibacterial activity of aminoglycoside. We identify 8-arm PEG-conjugated netilmicin (8-arm Netil) as a lead NETs-neutralizer from a library of multivalent aminoglycoside-displayed materials. When compared with 2- and 4-arm counterparts, 8-arm Netil exhibits potent antibacterial activity and high-affinity binding to DNA-histone chromatin complexes through stable multivalent noncovalent interactions, thereby suppressing NET-induced TLR4/TLR9 activation and macrophage inflammatory responses. In severe septic mice, intravenously administered 8-arm Netil preferentially accumulates in inflamed tissues, leading to improved survival protection, owing to the reduction of bacterial dissemination, NET accumulation, systemic cytokine production, and multiple-organ injury. These findings establish NET-associated DNA-histone chromatin complexes as actionable extracellular targets and demonstrate multivalent chromatin targeting as a rational material design strategy for selective NET neutralization and inflammation control in severe sepsis.

bioengineering↗

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2026

Immunomodulatory Effects of Insulin-Derived Fibrils from Infusion Pumps: Role of Phenolic Preservatives in Macrophage Activation

BackgroundProtein fibrillation represents a critical challenge in therapeutic insulin delivery, yet the structural determinants and immunological consequences of insulin-derived fibrils (IDFs) formed in the presence of phenolic preservatives remain poorly characterized. ObjectiveThis study investigated the structural characteristics of IDFs formed with (IDF (+)) and without (IDF (-)) phenolic preservatives and elucidated their differential immunomodulatory mechanisms in bone marrow-derived macrophages (BMDMs). MethodsIDF structural properties were characterized using Thioflavin T fluorescence and nanoparticle tracking analysis (Spectradyne nCS1). BMDMs were treated with serial dilutions of IDF (+), IDF (-), or m-cresol. Cytotoxicity, reactive oxygen species (ROS) production, MIP-1 levels, and expression of signaling pathways were quantified. ResultsStructural analysis revealed similar aggregation states between IDF (+) and IDF (-). However, IDF (+) induced greater cytotoxicity and ROS production than IDF (-), which produced minimal ROS. Both fibrils increased MIP-1 chemokine levels. Additionally, IDF (-) upregulated NRF2 whereas m-cresol downregulated STAT6 compared to control. Together, these results support the existence of distinct mechanisms of macrophage activation and suggest that protein aggregates can directly induce macrophage responses independent of ROS production. ConclusionsInsulin fibrils activate macrophage inflammatory pathways through ROS-independent mechanisms. Phenolic preservatives enhance fibril cytotoxicity and likely ROS production while differentially modulating inflammatory signaling. These findings suggest that strategies to remove or reduce the effects of IDFs in insulin infusion therapy may increase longevity and biocompatibility of these devices.

immunology↗

bioRxiv2026

Accurate de novo design of peptides from programming biophysical landscape

Peptides regulate virtually every cellular process and emerge as transformative modalities in bioengineering and therapeutics. However, the de novo design of functional peptides remains challenging, as peptide-protein interactions are governed by delicate and dynamic biophysics that are difficult to model, and experimental datasets are scarce. Here we present NeoPep, a generative deep-learning framework that encodes biophysical principles to accurately design functional peptides de novo. By integrating over 5 million peptide-protein complexes spanning experimentally determined, sequence mimics, and structure ensembles, NeoPep learns the complex biophysical landscape governing peptide function and enables its programmable control. In prospective application across 10 diverse and challenging targets, NeoPep generated potent peptide binders, agonists, and antagonists with hit rates of 12.5-66.7%, even in the absence of defined binding sites or structure information. Beyond de novo co-design, NeoPep supports standalone structure or sequence redesign, readily discriminating subtle context differences. In the structure redesign mode, it generates highly selective peptides with atomic-level conformational accuracy (C RMSD < 2.0 [A] to our solved cryo-EM structure). This structural precision circumvents the need for experimental structure determination, further accelerating iterative sequence redesign to yield a 43.3-fold improvement in potency. These findings establish a general framework for translating biophysical principles into actionable peptide functions, with broad implications for basic research, bioengineering, and medicine.

molecular biology↗

bioRxiv2026

Gene-Specific Analysis of Clonal Hematopoiesis Identifies ASXL1 as a Risk Factor for Lung Cancer

IntroductionClonal hematopoiesis of indeterminate potential (CHIP) is a recognized risk factor for hematologic malignancies, but its contribution to different types of solid cancers remains incompletely defined. MethodsHere, we performed a systematic, gene-specific analysis of CHIP across 19 common solid cancer types using two large population-based cohorts, the UK Biobank and All of Us with Cox proportional hazards models and nested case-control logistic models. ResultsWe demonstrate that the relationship between CHIP and solid tumors is highly cancer-type specific, with lung cancer exhibiting the strongest association. In lung cancer, this association is largely driven by ASXL1-mutant clones. Specifically, high variant allele fraction (high-VAF) ASXL1 conferring a significantly increased risk (hazard ratio = 3.2), and the associations remained robust after adjustment for age, sex, body mass index (BMI), smoking status, and genetic ancestry. Notably, ASXL1 CHIP was substantially enriched among smokers, and its association with lung cancer risk was restricted to ever-smokers, highlighting a key interaction between CHIP and environmental exposure. The enrichment of ASXL1 CHIP in lung cancer was further validated in two independent cancer-only cohorts, including MSK-IMPACT and TCGA. In addition, rare germline variant association analysis revealed that germline variation in ASXL1 had the strongest association with lung cancer susceptibility among all solid tumors. ConclusionsCollectively, our findings support a model in which smoking-associated expansion of ASXL1-mutant clones contributes to lung cancer development and suggest that gene-specific CHIP metrics may enhance risk stratification and early detection strategies.

bioinformatics↗

bioRxiv2026

Targeting cancer-associated cell surface RNAs with oligonucleotide-drug conjugates enables broad antitumor activity

Recent studies have revealed the presence of RNAs on mammalian cell surfaces, yet the linkage of cell surface RNAs (csRNAs) to cellular states and their potential as extracellular accessible drug targets remains unexplored. Here we develop Cell-surface and Intracellular RNAs Co-mapping (CIRCmap), a highly multiplexed in situ profiling approach that simultaneously detects thousands of cell-surface and intracellular RNAs at single-cell resolution. Using CIRCmap, we uncover that csRNA distributions are correlated with cellular states and identified cancer-associated csRNAs. Integrative analysis of cell-surface and intracellular RNAs within the same cells implies that the csRNAs undergo endocytosis and endolysosomal trafficking, which is further supported by perturbation experiments and co-localization visualization. We design oligonucleotide-drug conjugates (ODCs) that target cancer-associated csRNAs for endocytic delivery of cytotoxic payloads selectively to cancer cells. ODCs exhibit broad antitumor activity in cell lines and an in vivo mouse tumor model, opening a promising new avenue for targeted cancer therapy.

cell biology↗

bioRxiv2026

Postnatal Reprogramming Shapes Human Intestinal Epithelial Immune Competency

At birth, the intestine must rapidly adapt to enable nutritional function and immune microbial tolerance. Here, integrating single-cell multi-omics and spatial transcriptomics we define the circuits underpinning this process. We identify asynchronous developmental trajectories with postnatal epithelial reprogramming characterised by coordinated changes in metabolism, junctional structure and innate defence. At birth epithelial stem cells demonstrate dynamic enhancer remodelling, with accessibility often preceding transcription. Fetal stemness elements remain accessible despite reduced transcription across epithelial lineages, retaining plasticity potential. Post-natal epithelia experience sequential homing of myeloid cells followed by innate T cells with peri-epithelial B cells localising later in infancy. Using developmentally staged organoids, we show that epithelial responses to inflammatory stimuli are age-dependent and constrained in early life. We identify BHLHE40 as an early-life regulator that attenuates the impact of interferon- and NF-{kappa}B-driven signalling. Altogether we define the events driving epithelial licensing and barrier adaptation at birth and through infancy.

cell biology↗

bioRxiv2026

Therapeutic targeting inflammation linking periodontitis and atherosclerotic comorbidities using cell-free DNA-capturing nanomaterials

Periodontitis-associated systemic inflammation makes it a great challenge to explore therapeutic options applicable to periodontitis and atherosclerotic comorbidities. Here, we identify the crucial role of cell-free DNA (cfDNA) that underlies these comorbidities. Hypothesizing cfDNA as a therapeutic target, we engineer polyamidoamine dendrimer-functionalized nanomaterials to modulate such local-systemic inflammatory crosstalk. Periodontium-originated DNA can be systemically captured by cationic nanomaterials, and capturing cfDNA, whether locally or systemically, alleviates both periodontitis and atherosclerosis prior to severe atherosclerotic development in vivo. The transcriptomic and single-cell RNA sequencing analyses together reveal that cfDNA-capturing nanomaterials regulate inflammatory foam cell transformation in macrophages by modulating the expression of lipid-related foamy markers Spp1 and Fabp4. This study provides a proof of concept for cfDNA-driven periodontitis-atherosclerosis crosstalk, and offers a cfDNA-capturing nanoplatform for therapeutic intervention targeting periodontitis and atherosclerotic comorbidities in a holistic fashion.

immunology↗

bioRxiv2026

An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies

B cell-targeted therapies represent a transformative frontier for systemic lupus erythematosus (SLE) intervention, yet clinical recommendation of specific treatment is hampered by the challenge to perform head-to-head comparisons of efficacy-toxicity trade-offs and tissue-specific impacts in patients. To address this gap, an advanced Toll-like receptor 7 (TLR7) agonist-induced SLE model is developed in a NCG-M (NOD-Prkdcem26Cd52Il2rgem26Cd22Rosa26em1Cin(hCSF2&IL3&KITLG)/Gpt) human immune system (HIS) mice. This model enables parallel evaluation of multiple B cell-directed therapies within a controlled cohort study. It recapitulates core SLE pathologies--including immune effector cell augmentation, autoantibody production and glomerulonephritis--within 2 months, demonstrating greater severity and clinical fidelity than conventional pristane-induced systems. Validated through replication of clinical responses to rituximab and belimumab, the platform directly compares two emerging modalities: universal chimeric antigen receptor-T cells (UCAR-T) elicits delayed but profound B-cell reset correlating with superior reduction in renal pathology and autoantibodies, while T cell engagers (TCEs) mediate rapid yet partial B-cell depletion and transient efficacy. UCAR-T concurrently induces greater acute inflammatory responses, aligning with its distinct toxicity profile. By resolving therapy-specific effects on human immune dynamics and symptom control, this study empowers context-specific therapeutic selection for SLE, advancing tailored management strategies.

immunology↗

bioRxiv2026

Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance

Bacteriophage therapy is being explored as an alternate therapeutic approach for treating drug- resistant bacteria, including mycobacteria. However, rational phage dosing remains limited by scarce pharmacokinetic (PK) data and an incomplete understanding of tissue distribution. We performed dose-ranging studies in mice of three therapeutic mycobacteriophages (BPs{Delta}, ZoeJ{Delta}, Muddy) after intravenous (IV) and intratracheal (IT) administration. All phages behaved similarly. IV dosing produced biphasic kinetics with non-proportional exposure and declining tissue-to-plasma ratios, indicating saturable uptake and elimination. IT delivery yielded monophasic profiles with [~]390-fold higher lung exposure and [~]490-fold lower plasma exposure, supporting inhaled therapy for pulmonary mycobacterial infections. Using BPs{Delta} data, we developed a mechanistic PBPK model incorporating transcytosis, saturable host clearance, plasma elimination, and lymphatic transport. The model accurately predicted ZoeJ{Delta} and Muddy PK, enabled cross-species extrapolation, and showed that phage morphology influences disposition. This framework advances phage therapy toward model-informed, exposure-guided dose and route selection for multidrug-resistant bacterial infections.

pharmacology and toxicology↗

bioRxiv2025

NRF2-Dependent Anti-Inflammatory Activity of Indole via Cell Surface Receptor Signaling in Murine Macrophages

In this study, we report indoles anti-inflammatory effects to be AhR-independent in RAW 264.7 macrophages. To explore the possibility of indoles surface-receptor mediated signaling, we developed an indole-bovine serum albumin conjugate (I3B), which primarily engage cell surface receptors and has limited intracellular engagement. Treatment with 10 M of I3B led to a comparable reduction of TNF- production in LPS-stimulated RAW 264.7 macrophages to that observed with 500 M of free indole. Transcriptome profiling of I3B-treated LPS-stimulated RAW 264.7 macrophages revealed, I3B blunts pro-inflammatory response and induces gene signatures consistent with NRF2 activation. LPS-stimulated NRF2-/- Bone Marrow-derived Macrophages (BMM) treated with I3B, showed higher levels of pro-inflammatory cytokine production relative to non-treated BMM. To define the upstream pathways responsible for this NRF2-depedent response, we examined GPCR-mediated signaling and found that I3B engages a Gq-coupled receptor to induce PKC{delta} phosphorylation, and subsequent NRF2 phosphorylation. Our results suggest I3B signals through a surface-receptor in a NRF2-dependent manner to reduce inflammation in murine macrophages. TeaserA cell-impermeant indole conjugate inhibits inflammatory signaling in macrophages through an NRF2-dependent mechanism.

cell biology↗

bioRxiv2025

Reciprocal Homoeologous Replacement of MYB Factors Drives the Evolutionary Trade-off between Yield and Fiber Quality in Cotton

The long-standing phenotypic trade-off between Upland cotton (Gossypium hirsutum, high yield) and Sea Island cotton (G. barbadense, high quality) represents a major bottleneck in cotton breeding and industrialization. Despite rapid advances in genomics, the genomic structural variations driving the divergence of these two domestication strategies, and their subsequent impact on downstream transcriptional networks, remain unclear. This study integrates multi-tissue transcriptomic atlases spanning the full growth period with pan-genomic analyses of both Upland and Sea Island cotton, proposing a "Reciprocal Selective Retention (RSR)" strategy adopted by the two species during evolution. Transcriptomic analysis revealed that while the transcriptional chassis of the two species is highly conserved, a drastic "phase inversion" occurs during fiber development. Sea Island cotton appears to trade off for quality by specifically activating a "delayed elongation" module (at 20 DPA), whereas Upland cotton initiates a "precocious filling" program to pursue yield. Further Weighted Gene Co-expression Network Analysis (WGCNA), combined with genomic Presence/Absence Variation (PAV) analysis, identified a set of key transcription factors exhibiting a "3-vs-3" reciprocal loss pattern. Upland cotton specifically retained CRF10, WIND1, and MYB93, constructing a genetic foundation of "robust root system and strong regeneration" to support high yield. Conversely, Sea Island cotton specifically retained MYB111 and ERF105/017 to maintain long-staple characteristics and environmental buffering. Whole-genome structural variation and microsynteny analyses confirmed that these differences stem from asymmetric physical deletions (e.g., a 5 kb deletion in MYB111) or fragment sequence collapse (e.g., a 15.9 kb sequence divergence in MYB93) on homologous chromosomes. The RSR model proposed in this study not only offers a novel insight into the genetic roots of the negative correlation between yield and quality but also provides clear genomic targets for precision improvement using gene-editing technologies such as CRISPR.

genomics↗