Biology subjects

Tian, S.

Publications and source records attributed to Tian, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon

Pangenomes are increasingly critical for harnessing crop genetic diversity, yet their resolution and utility are often limited by insufficient sampling of high-quality genome assemblies. Here, we report a population-level watermelon super-pangenome constructed from 138 reference-grade assemblies, including 135 newly generated near-gapless genomes representing all seven watermelon species. The super-pangenome captures approximately one million structural variants (SVs), enabling accurate variant genotyping across ~900 watermelon accessions and substantially expanding variant discovery both across and within species. Broader sampling within the pangenome provides insights into genome evolution among watermelon species and sheds light on the origin of cultivated watermelon. SV-inclusive genome-wide association studies enhance trait mapping resolution and identify a copy number variation upstream of ClFCI1 that regulates flesh color intensity in a dosage-dependent manner. Leveraging this comprehensive variation map, we developed high-accuracy genomic prediction models for 18 agronomic traits. Together, our findings and genomic resources establish a foundational framework for dissecting complex traits and accelerating precision breeding in watermelon, while offering a valuable model for SV-resolved pangenomics in crop species.

plant biology↗

bioRxiv2025

Development of a replication-defective MPXV platform for fundamental and therapeutic research

The recent global outbreaks of mpox highlight the urgent need for both fundamental research and antiviral development. However, studying monkeypox virus (MPXV), with its large and complex genome, remains challenging due to the requirement for high-containment facilities. Here, we describe a novel strategy for de novo assembly of MPXV clade IIb genomes in bacterial artificial chromosomes using transformation-associated recombination cloning. Leveraging CRISPR-Cas9 and Lambda Red recombination, we engineered replication-defective MPXV particles with dual deletions of OPG96 (M2R) and OPG158 (A32.5L)--genes essential for virion assembly, that are capable of recapitulating key stages of the viral life cycle. Our work demonstrates the utility of replication-defective MPXV particles as a reliable platform for high-throughput antiviral discovery, offering significant advantages for both fundamental virology studies and therapeutic development against orthopoxviruses.

microbiology↗

bioRxiv2025

UniCure: A Foundation Model for Predicting Personalized Cancer Therapy Response

Predicting drug efficacy across diverse patient contexts remains a major challenge in oncology, as models trained on cancer cell lines often fail to capture patient-specific biology. Emerging biological foundation models and patient-derived technologies offer a promising solution. Here, we present UniCure, the first pre-trained foundation model integrating both omics and chemical foundation models (UCE and Uni-mol) to predict transcriptomic responses to drugs across diverse cellular and tissue contexts, enabling personalized cancer therapy and drug prioritization at the individual level. Rather than encoder/decoder used in traditional models, UniCure utilizes parameter-efficient fine-tuning (PEFT) techniques for optimizing the training process, a novel FlexPert module for modeling flexible drug-cell interactions, and a Maximum Mean Discrepancy (MMD) loss for learning unpaired data. Trained on over 1.8 million perturbation RNA-seq profiles over 22,000 compounds, 166 cell types, and 24 tissues, UniCure achieves high accuracy in predicting both dose-dependent responses and drug combination effects, demonstrating strong generalization across bulk and single-cell transcriptomic data. In particular, fine-tuning on our patient-derived tumor-like clusters and real-world data of 800 profiles enables UniCure to generate individualized therapeutic predictions on patients tissue samples. In addition, UniCure enables patient stratification based on the predicted drug responses, providing a new way for subtyping patients. UniCures drug prioritization was validated across over 1000 patients from pan-cancer cohorts and supported by experiments of candidate therapeutics. By enabling the potential to screen millions of compounds per patient at scale, UniCure represents a biologically grounded tool that could advance personalized precision oncology and accelerate drug discovery.

bioinformatics↗

bioRxiv2025

Characterization of intermolecular base pairing using AMT crosslinking in mammalian cells during oxidative stress

Cellular stress induces global translational repression, leading to exposure of RNA sequences that could engage in intermolecular base pairing. However, characterization of these interactions in stressed cells remains limited. Here, we coupled RNA crosslinking with biotin pulldown to probe intermolecular base pairing in mammalian cells during oxidative stress. We found that oxidative stress downregulates intermolecular base pairing of a reporter mRNA engineered to enhance detection of such interactions. Consistently, crosslinking-dependent intermolecular base pairing was not readily detected among candidate mRNAs that accumulate in stress granules - RNA-rich condensates that form during stress. Furthermore, chemical probing of base accessibility revealed that while RNA regions within these transcripts remain structured during stress, they increase in structural diversity in a manner dependent on oxidative stress and the stress granule nucleating proteins G3BP1 and G3BP2. This enhanced structural heterogeneity may help reduce a sustained exposure of interaction-prone RNA sequences during stress such as those prone to crosslinking. We propose that the combined downregulation of intermolecular base pairing and increased RNA structural diversity provides a mechanism to preserve normal function of RNAs during stress, while simultaneously enabling the reversible assembly of stress granules.

molecular biology↗

bioRxiv2025

APOBEC5: characterisation of a novel member of the AID/APOBEC protein family

The AID/APOBEC protein family is involved in diverse biological processes, most notably antiviral innate immunity, a function carried out by APOBEC3 (A3) in placental mammals. A3 is exclusive to this lineage, having emerged after the divergence from marsupials. This raises the question of how marsupials, which lack A3, defend against retroviruses. An uncharacterized A3 homologue, APOBEC5 (A5), is present in marsupial genomes and in some other vertebrate taxa. Here, we use in silico and in vitro approaches to investigate whether A5 serves as a functional antiviral counterpart to A3 in marsupials and whether marsupial genomes contain evidence of past A3-like activity against retroviral infections. We find that A5 was present in the last common ancestor of all jawed vertebrates but has been lost independently in multiple lineages. A5 exhibits unique structural and post-translational features not observed in APOBEC3 or other APOBEC proteins and has a broad subcellular and tissue distribution, suggesting a multifunctional role. Mutagenesis assays demonstrate that A5 functions as a DNA mutator and modestly restricts the infectivity of a model retrovirus, HIV-1, and that this activity is counteracted by the HIV-1 protein, Vif. Furthermore, analysis of the gray short-tailed opossum genome reveals distinct patterns of A3-like restriction in two groups of recently integrated retroviruses, providing direct evidence of an ongoing evolutionary conflict between marsupial APOBEC proteins and retroviruses. This study presents the first characterisation of A5 as a novel AID/APOBEC family member and reveals that marsupials possess an antiviral function homologous to placental A3, shedding light on the evolutionary dynamics of vertebrate antiviral immunity.

evolutionary biology↗

bioRxiv2025

A novel Hox gene promoter fuels the evolution of adaptive phenotypic plasticity

Adaptive phenotypic plasticity allows organisms to display distinct phenotypes in response to variable environments, but little is known about the genomic changes that promote the evolution of plasticity on a macroevolutionary scale. Combining spatial transcriptomics, comparative genomics, and genome editing, we show that temperature-mediated plasticity in the size of eyespot wing patterns in satyrid butterflies, a derived seasonal adaptation evolved [~]80 million years ago in this subfamily, is associated with the taxon-specific evolution of a novel promoter in the Hox gene Antennapedia (Antp). The promoter activates Antp expression specifically in satyrid eyespot center cells, sensitizes these cells to environmental temperatures, and plays a critical role in regulating satyrid eyespot size plasticity. Our study demonstrates that a taxon-specific cis-regulatory innovation in an ancestral developmental gene fueled the evolution of adaptive phenotypic plasticity across a clade of animals.

evolutionary biology↗

bioRxiv2025

Auto-downregulation of the florigen FT production prevents precocious flowering in plants

In many flowering plants, the developmental switch from vegetative growth to reproduction (flowering) is timed by seasonal changes in the length of daylight (photoperiod). Under inductive day lengths, the photoperiod pathway typically generates rhythmic expression of a transcriptional activator for florigen production. In the facultative long-day plant Arabidopsis thaliana, long-day exposure results in increasing buildup of the CONSTANS (CO) protein towards the end of daylight, and CO activates the expression of the major florigen gene FLOWERING LOCUS T (FT) to confer long-day induction of flowering. CO-mediated FT activation must be properly controlled to prevent an excessive florigen production and precocious flowering under inductive long days, but the underlying mechanism remains elusive. Here, we report an auto-repression mechanism to prevent excessive FT production in inductive photoperiods. We show that the transcription factor FD is expressed in leaf veins and complexes with FT to recognize several cis-regulatory DNA motifs in FT promoter. FT-FD antagonizes CO-mediated FT activation to feedback down-regulate FT expression and thus prevent its excessive induction by long-day signals, thereby precluding precocious transition to flowering. Furthermore, we found that in the facultative short-day plant soybean, an FT homolog directly represses its own expression. Thus, the auto-repression of FT or an FT homolog is a conserved mechanism to prevent excessive production of this potent floral regulator in plants, ensuring the floral transition at a proper time to balance vegetative growth with reproductive success and maximize plant production.

plant biology↗

bioRxiv2025

A pair of readers of histone H3K4 methylation recruit Polycomb repressive complex 2 to regulate photoperiodic flowering

In flowering plants, the transition from vegetative growth to reproduction or flowering, is often timed by seasonal changes in day length (photoperiod). In the model flowering plant Arabidopsis thaliana, the photoperiodic cue increasing day length or long day, through the photoperiod pathway, induces a daily rhythmic activation of the florigen gene FLOWERING LOCUS T (FT) to promote flowering. Under inductive long days (LDs), FT expression is activated around dusk, but to be repressed overnight and into the early afternoon the next day. The mechanism underlying the daily oscillation of FT repression to ensure long-day induction of flowering remains unclear. Here, we report that AtING1 and AtING2, Arabidopsis homologs of the mammalian Inhibitor of Growth (ING) proteins, read di- and tri-methylated histone 3 lysine 4 (H3K4me2/me3) on FT chromatin and further recruit Polycomb-repressive complex 2 (PRC2) to repress FT expression at night and into the early afternoon the next day, following FT activation at dusk in LDs. This prevents precocious flowering under inductive LDs. Our study reveals that a previously-undescribed chromatin-regulatory module: H3K4me2/me3-ING1/2-PRC2, which timely represses FT expression following the daily rhythmic FT activation at dusk by the long-day pathway, to prevent excessive FT expression and thus precisely control the timing of the transition to flowering in response to inductive photoperiodic signals.

plant biology↗

bioRxiv2025

Restoration of tumor suppressor protein with enhanced activity using engineered tRNAs to induce tumor regression

Cancer develops through a gradual accumulation of mutations including nonsense mutations in tumor suppressor genes (TSGs), which drive tumor proliferation and progression due to the impairment or complete loss of tumor suppressor protein function. The ability to restore functional tumor suppressor protein from mutant driver TSGs is a longstanding aspiration in cancer therapy, however, current strategies face formidable challenges in recovering proteins harboring heterogeneous mutations and circumventing dominant-negative effects exerted by endogenous mutant proteins. Therefore, the development of therapeutic interventions that are effective and generalizable across diverse nonsense mutations in cancer, to rescue endogenous mutant tumor suppressor proteins remains an urgent yet unmet need. Here we find that engineered suppressor transfer RNA (sup-tRNA) could overcome nonsense mutations in key driver tumor suppressor genes, such as TP53, thereby avoiding the dominant-negative effects through the restoration of endogenous mutant p53 with its original functions. Optimized sup-tRNA that we named super tRNA, enabling high-fidelity incorporation of desired amino acids, can further enhanced the transcriptional activity of p53 to suppress tumor cell proliferation. Moreover, we also establish a computational model to guide super tRNAs design, and demonstrate that super tRNA could effectively inhibit tumor growth by targeted readthrough of nonsense mutations in different tumor suppressor genes. In two xenograft models harboring nonsense mutant TP53, we observed up to a 70% reduction in tumor volume after lipid nanoparticle (LNP)-based sup-tRNA treatment, along with robust recovery of p53 expression and function, and no hematological or histological abnormalities detected. Our findings demonstrate the potential of sup-tRNA as a feasible and effective strategy to rescue and enhance tumor suppressor protein function, thereby preventing cancer development. As a novel therapeutic RNA, sup-tRNA provides a flexible strategy for targeting driver mutations in cancer, thereby expanding the potential of tRNA-based therapy in precision oncology.

bioengineering↗

bioRxiv2025

Methylome and transcriptome analysis reveals the impact of psychological stress on the skin

Psychological stress has been shown to impact skin and DNA methylome, but the mechanisms are poorly understood. Here, we collected multi-omics data from 60 stressed and 60 relaxed individuals to test the hypothesis that psychological stress may impact skin via epigenetic modification and downstream altered gene expression. Each volunteer completed a series of questionnaires and assessments to measure their psychological stress levels and skin condition. Suction blister samples were collected for analyze skin cytokines, DNA methylome, and transcriptome. The dataset generated allowed for the identification of 289 differentially methylated probes(DMPs) and 10 differentially expressed genes (DEGs). Integration of methylation and expression data revealed seven functional epigenetic modules(P<0.05), which were involved in the glutamatergic synapse. In line with previous studies on the prefrontal cortex/hippocampus, we found that psychological stress also affects the glutamatergic synapse in the skin. There was no significant group difference in cytokines, while the stressed group had more severe skin darkening (P=7.36x10-6). This study provides important insight into the impact of psychological stress on the skin and contributes a comprehensive multi-omics dataset resource for the healthy epidermis.

genetics↗

bioRxiv2025

Investigating Gene Expression Noise Reduction by MicroRNAs and MiRISC Reinforcement by Self-Feedback Regulation of mRNA Degradation

The microRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably the rate-limiting step of the miRNA-mediated regulatory subsystem - a major noise reducing, though metabolically costly, mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto its own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. In this paper, our mathematical modeling predicts that mRNA expression noise exhibits a negative correlation with the degradation rate (Kdeg) and is attenuated by self-feedback control of degradation. We also calculated Kdeg and expression noise of mRNAs detected in a total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher Kdeg values accompanied by reduced inter-cell expression noise, confirming the operational trade-off between noise suppression and the increased metabolic/energetic costs associated with producing these mRNAs subjected to accelerated degradation and translational inhibition. Moreover, consistent with the Kdeg self-feedback control model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In summary, mathematical-modeling and total-RNA scRNA-seq data-analyses provide evidence that negative self-feedback regulation of mRNA degradation reinforces miRISC, the core machinery of the miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first study to concurrently analyze mRNA degradation dynamics and expression noise, and to demonstrate noise reduction by self-feedback regulation of mRNA degradation.

systems biology↗

bioRxiv2025

Free-Form Microfluidic Microneedle Array Patches

Personalized biomedical devices, such as microneedle array patches (MAPs), offer a promising transdermal drug delivery technology, providing a safe, painless, and self- administered alternative to traditional hypodermic injections. Despite their potential for precise therapeutic release, MAP adoption has been limited by challenges in payload capacity, treatment versatility, and manufacturing scalability. To address these issues, we integrated microfluidic channel designs with MAP technology, enhancing its functionality for delivering a range of payloads, from liquid therapeutics to solid-state cargos, at tunable volumes. Using injection continuous liquid interface production (iCLIP), a novel additive manufacturing approach, we fabricated high-resolution microfluidic MAPs with complex designs. Inspired by the stingers and fangs of various venomous animals, we developed a biomimetic microneedle design that prevents clogging, enhances mechanical strength, and eliminates needle leakage, thereby improving therapeutic delivery efficiency. Our technology reliably delivers multiple distinct payloads, enables combinational mixing, and enables point-of-care reconstitution of solid-state payloads. TeaserLeveraging biomimetic design and advanced 3D printing, we developed high-resolution microfluidic microneedle array patches (MAPs) that overcome payload and scalability challenges, offering a versatile and efficient platform for precise transdermal drug delivery.

bioengineering↗

bioRxiv2024

Language model-guided anticipation and discovery of unknown metabolites

Despite decades of study, large parts of the mammalian metabolome remain unexplored. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks within human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains a low-throughput endeavor. Biochemical large language models have transformed the interpretation of DNA, RNA, and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here, we present an approach that leverages chemical language models to discover previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns the latent biosynthetic logic embedded within the structures of known metabolites and exploits this understanding to anticipate the existence of as-of-yet undiscovered metabolites. Prospective chemical synthesis of metabolites predicted to exist by DeepMet directs their targeted discovery. Integrating DeepMet with tandem mass spectrometry (MS/MS) data enables automated metabolite discovery within complex tissues. We harness DeepMet to discover several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to accelerate the mapping of the metabolome.

bioinformatics↗

bioRxiv2024

Exploring methanogenic archaea and their thermal responses in the glacier-fed stream sediments of Rongbuk River Basin, Mt. Everest

Glacier-fed streams (GFS) are emergent sources of greenhouse gas methane, and methanogenic archaea in sediments contribute largely to stream methane emissions. However, little is known about the methanogenic communities in GFS sediments and their key environmental driving factors. This study analyzed stream sediments from the Rongbuk River basin on Mount Everest for methanogenic communities and their temperature responses through anaerobic microcosm incubations at 5{degrees}C and 15{degrees}C. Diverse methanogens were identified, including acetoclastic, hydrogenotrophic, and methylotrophic types. Substantial methane and CO2 production were detected across altitudes and increased significantly at 15{degrees}C, with both methane and CO2 production rate negatively correlated with altitude. While temperature sensitivity of CO2 production but not CH4 showed a negative altitude correlation. Methanogens increased substantially over long-term incubation, dominating the archaeal community. At 15{degrees}C, the relative abundance of several methanogenic groups was strongly correlated with altitude, with positive correlations observed for Methanomassiliicoccaceae and Methanoregulaceae, and negative correlations for Methanocellaceae and Methanotrichaceae, respectively. Besides altitude, factors like phosphorus, C-to-N ratio, and pH also affected methanogenic structure, methane and CO2 production, and temperature sensitivities. This study offers new insights into methanogens and methane production in GFS sediments, improving our understanding of GFS carbon cycling and its potential responses to climate change.

ecology↗

bioRxiv2024

D-lactate derived from intestinal bacteria drives lysine D-lactylation to modulate transcription in liver cells

Emerging evidence indicates that the accumulated D-lactate (D-la) from intestinal bacteria induces diverse effects in human intestinal injury diseases. However, its regulatory mechanism and functional consequence remain unclear. Here, we show that the secreted D-la induces lysine D-lactylation (K-Dla) to modulate transcription in host cells. We uncover K-Dla in HepG2 cells stimulated by D-la from E. coli secretions. Then, we confirm the occurrence of D-la-driven K-Dla by four orthogonal approaches. We further validate that the existence of K-Dla in organisms by detecting the mouse liver and human intestinal tissue. Besides, we demonstrate a SCOT1-catalyzed biosynthetic pathway of D-lactyl-CoA, serving as a key donor for K-Dla. Next, we identify the K-Dla landscape with 2895 sites and further suggest the regulation of histone K-Dla in transcription by MNase ChIP-seq and RNA-seq assays. Finally, we show the potential effect of K-Dla on inhibiting the hepatocellular carcinoma cell proliferation. In summary, we report that the secreted D-la can induce K-Dla to regulate transcription, providing a new insight into the function of D-la secreted by gut microbiota and the effect of protein chemical modifications induced by bacterial secretions.

molecular biology↗

bioRxiv2024

Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression

p53 prevents tumor initiation and progression via transcriptional regulation of target gene networks. Here, we find that cancer-associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes the outgrowth of cancer cells with transcriptionally active, wild-type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG)-dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression, resulting in disabled upregulation of targets that execute tumor suppression. Specifically, mutant IDH disrupts the expression of pro-apoptotic p53 targets that enable p53-dependent tumor regressions, including the death ligand receptor Fas. Pharmacological inhibition of mutant IDH in TP53 wild-type cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy-induced apoptosis. Therefore, we implicate the disruption of p53 target gene regulation as a reversible, oncogenic feature of cancer-associated IDH mutations. SIGNIFICANCEWe find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.

cancer biology↗

bioRxiv2024

Multivalent administration of dengue E dimers on liposomes elicits type-specific neutralizing responses without immune interference

The four serotypes of dengue virus (DENV1-4) are a major health concern putting 50% of the global population at risk of infection. Crucially, DENV vaccines must be tetravalent to provide protection against all four serotypes because immunity to only one serotype can enhance infections caused by heterologous serotypes. Uneven replication of live-attenuated viruses in tetravalent vaccines can lead to disease enhancement instead of protection. Subunit vaccines are a promising alternative as the vaccine components are not dependent on viral replication and antigen doses can be controlled to achieve a balanced response. Here, we show that a tetravalent subunit vaccine of dengue envelope (E) proteins computationally stabilized to form native-like dimers elicits type-specific neutralizing antibodies in mice against all four serotypes. The immune response was enhanced by displaying the E dimers on liposomes embedded with adjuvant, and no interference was detected between the four components.

microbiology↗

bioRxiv2024

Brain and gonadal genes are differentially expressed in Bicyclus anynana butterfly larvae that learned a heritable novel food odor preference

Bicyclus anynana butterfly larvae learn to prefer novel odors added to their plant food and transmit those learned preferences to the next generation. However, the molecular mechanisms regulating the inheritance of this acquired preference remain unexplored. Here we examined how larval diet affected gene expression patterns in the larval brain as well as the gonads of adults to explore a potential genetic basis of this inheritance. We fed B. anynana larvae leaves coated with a novel banana odor (isoamyl acetate), or with a control solution, and performed five choice assays on individual larvae during their development to identify individuals that showed a majority preference for the treatment odor they were fed with. We then dissected male and female larval brains, adult spermatophores, or adult oocytes from those individuals, and profiled mRNA in all tissues and micro-RNA (miRNA) expression in oocytes only. Our results show that there are 83 differentially expressed genes (DEGs) across all tissue types in odor and control groups, of which 23 play roles in metabolism, transcription, response to various chemical stimuli, and olfactory pathways. MiRNAs did not differ in expression across diet treatments, but we discovered 57 novel miRNAs in oocytes. The DEGs in gonads are potential epigenetic factors that can regulate the inheritance of a learned odor preference. Still, caution is required as there was no overlap between DEGs across male and female brains, as well as male and female gonads.

genomics↗