Biology subjects

Ye, G.

Publications and source records attributed to Ye, G..

At least 19 recordsLinked to original sources

bioRxiv2026

CDX2 Drives Divergent Regional Programs During Intestinal Development and Redeploys Them During Regeneration

Region-specific transcription factors (TFs) establish small intestinal and colonic identity, yet what activates their region-specific expression during development is unresolved. Moreover, discrete fetal gene sets reactivate during post-injury regeneration, but their full scope, and what reactivates the programs required to restore regional identity and tissue structure, remain unclear. By determining CDX2 and partner TF binding, enhancer activity, and gene expression dynamics across intestinal regions, in stem and differentiating cells, and through development and adult regeneration, here we show that CDX2, despite uniform expression across the fetal and adult intestinal epithelium, organizes a hierarchical enhancer network. This network cooperates with partner factors such as CTCF to establish a shared, plastic fetal enhancer landscape, which resolves into region-specific programs upstream of regional TFs. During regeneration, rather than reactivating a general fetal state, CDX2 selectively rebinds many region-specific and common enhancers for genes associated with fetal cell-motility and tissue-morphogenesis signatures along with a more recently active adult stem-cell program, each deployed across distinct crypt tiers. CDX2 thus functions as a central, context-responsive regulator, deploying fetal, adult stem-cell differentiation, and regenerative programs as tissue context requires.

developmental biology↗

bioRxiv2026

Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences

Peripheral innervation declines with age, but whether this process is sexually dimorphic and whether it reflects neuronal degeneration or deterioration of nerve-target interactions remain unclear. Using mouse skin as a defined neuroeffector system, we show that sympathetic aging is strongly sexually dimorphic, with greater denervation in aged males. Skin-projecting sympathetic neurons remain intact, indicating that denervation reflects distal axon withdrawal rather than neuronal loss. Nerve-target interactions and the arrector pili muscle niche deteriorate with age, predominantly in males. Aged sympathetic neurons retain NGF responsiveness, and restoring NGF within arrector pili muscles promotes sympathetic reinnervation and hair regeneration in aged males. Genetic and endocrine models show that divergent aging trajectories are associated with gonadal rather than chromosomal sex and are attenuated by early gonadectomy. Together, these findings identify sympathetic aging as a reversible, sexually dimorphic distal axonopathy shaped by the target environment and gonadal influences.

developmental biology↗

bioRxiv2026

Regulatory co-option of a homeobox gene drives parasitoid venom evolution

How gene regulatory networks are rewired to generate phenotypic and functional innovation remains a central question in evolutionary biology. Parasitoid wasp venoms provide a powerful system for addressing this question, as their repertoires evolve rapidly through extensive lineage-specific turnover, yet the regulatory principles underlying such flexibility are largely unknown. Here we integrate tissue-resolved transcriptomic, chromatin-accessibility and histone-modification profiling to reconstruct the venom regulatory network of the parasitoid wasp Pteromalus puparum. We show that venom expression is embedded in distinct chromatin states and shaped by regulatory elements associated with venom-gland transcription. Comparative and functional analyses support a general model in which regulators related to the endoplasmic reticulum stress and unfolded protein response pathways have been repeatedly recruited to venom regulation across venomous lineages. Unexpectedly, we identify the recently co-opted homeobox gene Lbx as a lineage-specific hub that regulates more than half of venom genes and is linked to enhancer evolution. These results reveal a nested model of venom regulatory evolution, in which an ancestral secretory programme provides a reusable regulatory backbone, while newly co-opted homeobox gene specify a lineage-specific venom expression. Our study highlights regulatory co-option as a mechanism by which conserved developmental genes can acquire new physiological functions during adaptive evolution.

evolutionary biology↗

bioRxiv2026

NINJ1 mediates hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion injury (IRI) results from interrupted perfusion to the liver and contributes to acute liver dysfunction such as following liver transplantation. Lytic cell death pathways are major drivers of IRI and the subsequent inflammatory response. The transmembrane protein ninjurin-1 (NINJ1) was identified as the key executor of terminal plasma membrane rupture across multiple lytic cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1-mediated lytic cell death drives IRI and that its therapeutic inhibition would mitigate liver IRI. Using human liver specimens, we found that NINJ1 is highly expressed in human liver tissue and that its activation correlates with early allograft dysfunction in patients undergoing liver transplantation. Utilizing a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute liver injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout both had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are highly susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. These data position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for organ preservation during liver transplantation.

immunology↗

bioRxiv2026

Promoter editing of starch branching enzyme IIb and granule-bound starch synthase I balances resistant starch content and amylose content in rice

Increasing attention is being focused on the glycemic index (GI) of daily food for humans, and the resistant starch content (RSC) is an important indicator of GI for starch-rich staple foods. In recent years, some studies revealed that the loss function of single or multiple key enzymes in the primary pathway of starch synthesis substantially increases RSC in rice, such as starch branching enzyme IIb (BEIIb) and soluble starch synthase IIIa (OsSSIIIa). However, a noteworthy negative characteristic of these high RSC mutants is the substantially increased amylose content (AC). AC as a major determinator of rice eating quality, must not be higher than an acceptable limit for most consumers. To solve this problem, in this study, we adopted two promoter editing (PE) editing strategies to develop rice germplasms with a better balance of RSC and AC: one is to edit the promoter of BEIIb in a low AC rice variety, another is to edit the promoter of Waxy (Wx) gene in a BEIIb loss of function mutant. Using AC[≤]20%, which is the range of premium quality rice in China as a criteria, we finally obtained 2 homozygous lines with significantly increased RSC ([≥]5%) in the NG46 background by promoter editing of BEIIb and 1 homozygous line in the YouTang2 (YT2, a BEIIb mutant) background by promoter editing of Wx gene. Further analysis revealed that AC and the amount of long-chain branches of amylopectin are positively correlated with RSC in the population of BEIIb PE lines. However, unexpectedly, the Wx PE-line with substantially decreased AC (17.7%) also showed significantly increased RSC (16.9%). Our study not only produces useful germplasms for the high RSC rice breeding in the future but also provides an insight into understanding the relationship between AC and RSC in defective BEIIb rice.

plant biology↗

bioRxiv2026

Epigenetic Gatekeeping of Intestinal Stem Cell Transformation

Widespread cell plasticity recognized in fetal intestinal epithelium is preserved in limited fashion in Wnt-responsive adult stem cells and contributes to tumour initiation, progression, and relapse. It is unclear which epigenetic features maintain stem-cell properties, restrict adult expression of fetal genes, and are attenuated in tumours, allowing non-stem cells to replenish targeted tumour stem cells. Here we show that reversible stemness in normal adult intestinal crypt cells hinges on a dynamic balance between activating H3K27ac and repressive H3K27me3 marks. Cells that leave the Wnt-rich stem-cell niche normally acquire H3K27me3 at thousands of stemness-associated enhancers. Constitutive tumourigenic Wnt activity transforms Apc-/- intestinal stem cells by gradual erosion of H3K27me3 at select enhancers and extends stem-like properties beyond usual anatomic confines; continued depletion of H3K27me3 reactivates enhancers that control growth and expression of a wider swath of fetal genes than appreciated previously. Subsequent focal DNA demethylation at expanded superenhancer domains is associated with tumour growth. Human colorectal cancers also carry evidence of this epigenetic rewiring. Accelerated H3K27me3 loss in mice hastens, and its preservation delays, activation of stemness-related enhancers, superenhancers, and tumour progression. During transformation, H3K27me3 loss at enhancers erases a crucial distinction between stem and non-stem populations, endowing the latter with stemness and providing an explanation for tumour resistance to cancer stem cell targeting. Thus, H3K27me3 at Wnt-responsive enhancers is an intrinsic barrier to intestinal tumourigenesis and aberrant reactivation of hundreds of fetal genes.

cancer biology↗

bioRxiv2025

A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation

The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in a previously uncharacterized pocket of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication 100-fold in the lungs of XBB.1.5-infected mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.

microbiology↗

bioRxiv2025

A niche-dependent redox rheostat regulates epithelial stem cell fate in the distal colon

The niche environment surrounding intestinal stem cells (ISCs) varies along the length of intestine and provides key cues that regulate stem cell fate. Here, we investigated the role of cellular redox balance in colonic ISC function. We show that hypoxia and Wnt signaling synergize to restrict the reactive oxygen species (ROS) generating enzyme NADPH oxidase 1 (NOX1) to the crypt base in the distal colon. NOX1 function maintains a more oxidative cell state that licenses cell cycle entry, altering the balance of asymmetric stem cell self-renewal and directing lineage commitment. Mechanistically, cell redox state directs a self-reinforcing circuit that connects hypoxia inducible factor 1 (HIF1)-dependent signaling with regulation of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1). Our studies show that cellular redox balance is a central and niche-dependent regulator of epithelial homeostasis and regeneration and provide a basis for understanding disease propensity in the distal large intestine. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/634856v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@107798aorg.highwire.dtl.DTLVardef@1bc9013org.highwire.dtl.DTLVardef@96d56aorg.highwire.dtl.DTLVardef@95268d_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIThe balance of cycling intestinal stem cells (ISCs) versus committed epithelial cells in the uniquely hypoxic niche of the distal colon is regulated by NADPH oxidase 1 (NOX1) dependent H2O2 both at homeostasis and during regeneration. C_LIO_LIPhysiological increase in cellular H2O2 favors maintenance of glycolysis in ISCs for self-renewal through regulation of isocitrate dehydrogenase 1 activity. C_LIO_LIMaintenance of the increased cellular oxidative state stabilizes HIF1 through a re-enforcing metabolic circuit. C_LIO_LIA shift from a relatively oxidative to a reductive cell environment in distal colonic ISCs leads to decreased progression through the cell cycle and altered cell fate determination. C_LI

cell biology↗

bioRxiv2024

Large-scale genome analyses provide insights into Hymenoptera evolution

The order Hymenoptera includes a large number of species with diverse lifestyles and is known for its significant contributions to natural ecosystems. To better understand the evolution of this diverse order, we performed large-scale comparative genomics on 131 species from 13 superfamilies, covering most representative groups. We used these genomes to reveal an overall pattern of genomic change in terms of gene content and evolutionary rate throughout hymenopteran history. We identified genes that possibly contributed to the evolution of several key innovations, such as parasitoidism, wasp-waist, sting, and secondary phytophagy. We also discovered the distinct genomic trajectories between the clade containing major parasitoid wasps (Parasitoida) and stinging species (Aculeata) since their divergence, which are involved in many aspects of genomic change, such as rapidly evolving gene families, gene gain and loss, and metabolic pathway evolution. In addition, we explored the genomic features accompanying the three independent evolution of secondary phytophagy. Our work provides insights for understanding genome evolution and the genomic basis of diversification in Hymenoptera.

genomics↗

bioRxiv2024

DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes

Precise spatiotemporal and cell type-specific gene expression is essential for proper tissue development and function. Transcription factors (TFs) guide this process by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of TFs. However, how TFs navigate various chromatin features and selectively bind a small portion of the millions of possible genomic target loci is still not well understood. Here we show that Cdx2 - a pioneer TF that binds distinct targets in developing versus adult intestinal epithelial cells - has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic and fetal Cdx2 target loci and the specifically methylated state of the CpG during development allows selective Cdx2 binding and activation of developmental enhancers and linked genes. Conversely, demethylation at these enhancers prohibits ectopic Cdx2 binding in adult cells, where Cdx2 binds its canonical motif without a CpG. This differential Cdx2 binding allows for corecruitment of Ctcf and Hnf4, facilitating the establishment of intestinal superenhancers during development and enhancers mediating adult homeostatic functions, respectively. Induced gain of DNA methylation in the adult mouse epithelium or cultured cells causes ectopic recruitment of Cdx2 to the developmental target loci and facilitates cobinding of the partner TFs. Together, our results demonstrate that the differential CpG motif requirements for Cdx2 binding to developmental versus adult target sites allow it to navigate different DNA methylation profiles and activate cell type-specific genes at appropriate times. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/579850v3_ufig1.gif" ALT="Figure 1"> View larger version (99K): org.highwire.dtl.DTLVardef@12d2253org.highwire.dtl.DTLVardef@289371org.highwire.dtl.DTLVardef@1e81b4borg.highwire.dtl.DTLVardef@157e322_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Genomic signatures of the evolution of loss of egg yolk in parasitoid wasps

Trait regression and loss have occurred repeatedly in numerous lineages throughout evolutionary history in response to changing environments. In parasitoid wasps, a mega-diverse group of hymenopteran insects, loss or reduction of yolk in the egg has been reported in many species. This phenotypic change likely evolved as a response to the shift from ectoparasitism to endoparasitism. However, the genetic basis of this trait and the impact of its loss on genome evolution remain poorly understood. Here, we performed a comparative genomic analysis of 64 hymenopteran insects. The conserved insect yolk protein gene vitellogenin (Vg) underwent five independent loss events in four families, involving 23 of the analyzed endoparasitoid species. Whole-genome alignment suggested that Vg loss occurred during genome rearrangement events. Analysis of Vg receptor gene (VgR) loss, selection, and structural variation in lineages lacking Vg demonstrated functional biases in the patterns of gene loss. The ectoparasitism to endoparasitism transition did not appear to be the primary driver of Vg loss or the subsequent VgR evolution. A number of parallel and convergent genomic changes were observed between Vg-loss lineages, including gene family evolution and selection of genes related to transport, development, and metabolism. These changes may have facilitated embryonic development without the yolk in these lineages. Together, these findings reveal the genomic basis underlying a unique trait loss in parasitoid wasps. More broadly, this study enhances our understanding of yolk loss evolution outside the class Mammalia, highlighting a potential evolutionary trend arising from the availability of an alternative nutrient source for embryonic development.

evolutionary biology↗

bioRxiv2023

CSTA: A Biomarker Regulating Esophageal Stricture Epithelial Barrier, Potential Medication Target

Esophageal strictures resulting from ESD/EMR in the esophagus are distressing, with uncertain causes and treatments due to epithelial barrier dysfunction. We explored cystatin A (CSTA) as a novel biomarker for the esophageal epithelial barrier. CSTA regulates the barrier and is influenced by tacrolimus (FK506). Analyzing biopsy samples by proteomics, we identified CSTA as an esophageal epithelial biomarker. Knocking down CSTA reduced responsiveness to triamcinolone acetonide (TA) and lowered expression of proteins related to cell-cell junctions and barrier function during inflammation. These findings suggest that down-regulate CSTA weakens tight junctions and the esophageal barrier, leading to strictures. Notably, FK506 showed promise in rescuing CSTA-knockdown cells by increasing the expression of proteins related to cell-cell junctions and barrier function. This highlights FK506 as a potential therapy for esophageal strictures in patients with CSTA mutations.

cell biology↗

bioRxiv2023

Comprehensive analyses of 1771 transcriptome from seven tissues enhance genetic and biological interpretations of maize complex traits

By analyzing 1771 RNA-seq datasets from seven tissues in a maize diversity panel, we explored the landscape of multi-tissue transcriptome variation and evolution patterns of tissue-specific genes, and built a comprehensive multi-tissue gene regulation atlas to understand the genetic regulation of maize complex trait. Using transcriptome-wide association analysis, we linked tissue-specific expression variation of 45 genes to variation of 11 agronomic traits. Through integrative analyses of tissue-specific gene regulatory variation with genome-wide association studies, we detected relevant tissue types and candidate genes for a number of agronomic traits, including leaf during the day for anthesis-silking interval (GRMZM2G093210), leaf during the day for kernel Zeinoxanthin level (GRMZM2G143202), and root for ear height (GRMZM2G700665), highlighting the contribution from tissue-specific gene expression to variation of agronomic trait. Our findings provide novel insights into the genetic and biological mechanisms underlying complex traits in maize, and the multi-tissue regulatory atlas serves as a primary source for biological interpretation, functional validation, and genomic improvement of maize.

genetics↗

bioRxiv2023

A parasitoid serpin gene that disrupts host immunity shows adaptive evolution of alternative splicing

Alternative splicing (AS) is a major source of protein diversity in eukaryotes, but less is known about its evolution compared to gene duplication (GD). How AS and GD interact is also largely understudied. By constructing the evolutionary trajectory of a serpin gene PpSerpin-1 (Pteromalus puparum serpin 1) in parasitoids and other insects, we found that both AS and GD jointly contribute to serpin protein diversity. These two processes are negatively correlated and show divergent features in both protein and regulatory sequences. Furthermore, parasitoid wasps exhibit higher numbers of serpin protein/domains than nonparasitoids, resulting from more GD but less AS in parasitoids. Nevertheless, PpSerpin-1 shows an exon expansion of AS compared to other parasitoids. We find that several isoforms of PpSerpin-1 are involved in the wasp immune response, have been recruited to both wasp venom and larval saliva, and suppress host immunity. In summary, we report the differential features of AS and GD in the evolution of insect serpins and their associations with the parasitic life strategy, and we provide an example of how a parasitoid serpin gene adapts to parasitism through AS.

evolutionary biology↗

bioRxiv2022

The Cation/H+ exchanger OsCAX2 is involved in cadmium tolerance and accumulation through vacuolar sequestration in rice

Excessive cadmium (Cd) in rice grains is a serious food safety problem. The development of Cd-safe varieties requires the identification of germplasms and genes with major effect on Cd accumulation but without negative effects on other important traits. Here, we reported that OsCAX2, a member of the rice Cation/H+ exchanger (CAX) family, is an important Cd transporter. OsCAX2 encodes a tonoplast-localized protein and is strongly upregulated by Cd, mainly expresses in root exodermis, parenchyma in cortex, endodermis and stele cells. Depletion of OsCAX2 resulted in enhanced Cd sensitivity and root-to-shoot translocation in rice, while overexpression of OsCAX2 significantly increased Cd tolerance and reduced Cd transport by promoting root Cd influx and vacuolar storage, which ultimately reduced Cd transport via xylem. OsCAX2 also had significant effects on tissues/organs distribution of Cd but had no effects on grain yield and agronomic traits. Importantly, the OsCAX2 overexpressing lines had more than 70% lower grain Cd accumulation, increased iron (Fe), zinc (Zn) and manganese (Mn) and reduced copper (Cu) accumulation. Therefore, OsCAX2 is an ideal gene for developing Cd-safe rice varieties via transgenic approach.

plant biology↗

bioRxiv2022

Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung

Bacillus Calmette-Guerin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). TII is associated with innate immune cells being in a hyper-responsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine-induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive amounts of progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms remain unknown. Here we show for the first time that s.c BCG vaccine-induced TII provides enhanced heterologous innate protection against pulmonary S. pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by accelerated neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens.

immunology↗

bioRxiv2021

A generic sequential stimulation adapter for reducing muscle fatigue during functional electrical stimulation

BackgroundClinical applications of conventional functional electrical stimulation (FES) administered via a single electrode is limited by rapid onset neuromuscular fatigue. "Sequential" (SEQ) stimulation, involving rotation of pulses between multiple active electrodes, has been shown to reduce fatigue compared to conventional FES. However, there has been limited adoption of SEQ in research and clinical settings. MethodsThe SEQ adapter is a small, battery-powered device that transforms the output of any commercially available electrical stimulator into SEQ stimulation. We examined the output of the adaptor across a range of clinically relevant stimulation pulse parameters to verify the signal integrity preservation ability of the SEQ adapter. Pulse frequency, amplitude, and duration were varied across discrete states between 4-200 Hz, 10-100 mA, and 50-2000 s, respectively. ResultsA total of 420 trials were conducted, with 80 stimulation pulses per trial. The SEQ adapter demonstrated excellent preservation of signal integrity, matching the pulse characteristics of the originating stimulator within 1% error. The SEQ adapter operates as expected at pulse frequencies up to 160 Hz, with a noted failure mode at 200 Hz. ConclusionThe SEQ adapter represents an effective and low-cost solution to increase the utilization of SEQ in existing rehabilitation paradigms.

bioengineering↗

bioRxiv2021

Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.

immunology↗