Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 253 records · Page 14Linked to original sources

bioRxiv2025

PD-1 signaling is essential for the early accumulation of HBV-specific CD8+ T cells during HBV infection

Background & AimsProgrammed cell death Protein 1(PD-1) is one of the key inhibitory receptors that regulates CD8 T cell exhaustion during chronic viral infection. However, the role of PD-1 in modulating effector T cell differentiation and function during early phase of hepatitis B virus (HBV) infection remains poorly defined. MethodsUsing adoptive transfer of wild-type or PD-1 KO HBV-specific TCR transgenic (C93-TCRtg) CD8 T cells, flow cytometry, and transcriptome sequencing, we systematically profiled early PD-1 dynamics in splenic and intrahepatic T cells and evaluated how PD-1 deficiency shapes anti-HBV T cell responses in acute self-resolving (AR) and chronic (CH) HBV mouse models. ResultsAcute HBV infection induced sustained PD-1 upregulation on intrahepatic/splenic CD8 T cells, which predominantly exhibited an effector phenotype. PD-1 cells displayed enhanced proliferation, cytotoxicity, and effector cytokine production compared to PD-1- counterparts. Adoptive transfer of PD-1 KO C93-TCRtg CD8 T cells resulted in significantly impaired early expansion in both spleen and liver during acute infection, accompanied by reduced granzyme B expression while maintaining IFN-{gamma}, TNF-, or IL-2 production. Transcriptomic analysis revealed that PD-1 deficiency was associated with the upregulation of apoptosis gene signatures. In chronic HBV infection, PD-1 KO cells failed to expand long-term and exhibited exacerbated exhaustion evidenced by a loss of IFN-{gamma} production. ConclusionsPD-1 is essential for the early expansion and survival of HBV-specific CD8 T cells during acute infection and does not suppress their effector cytokine function. Its absence impairs proliferation and promotes exhaustion of HBV-specific CD8 T cell in chronic infections. Impact and implicationsOur study redefines PD-1s role in acute HBV infection. Rather than merely constraining effector function, PD-1 is essential for the early expansion and survival of HBV-specific CD8+ T cells, acting as a safeguard against activation-induced apoptosis. The context-dependent functions position PD-1 as a critical rheostat calibrating the magnitude and quality of the antiviral CD8+ T cell response, with significant implications for immunotherapeutic strategies targeting this pathway in hepatitis B.

immunology↗

bioRxiv2025

Probing the genomic and proteomic basis of encystment in Oxytricha granulifera

Protozoan encystment is a crucial survival strategy for resisting environmental stresses, yet its molecular mechanisms remain poorly understood due to limited genomic resources and lack of integrated multi-omics analyses in model ciliates. In this study, we aimed to elucidate the molecular mechanisms underlying the encystment process in Oxytricha granulifera by sequencing and assembled its genome, and by conducting comprehensive transcriptome, proteome and morphology analyses to reveal gene expression and morphologic changes between vegetative and cyst stages. Morphological observation revealed ciliary dedifferentiation and cyst-wall formation during encystment, events respectively supported by the downregulation of microtubule dynamics related genes and the upregulation of vesicle transport related genes in cyst stage. Expanded gene families for carbohydrate metabolism, autophagy and cellular acidification align with the species mucocyst signature and their observed autophagic clearance, hinting at previously unrecognized mechanisms underlying cyst formation. Elevated expression of the ubiquitin-proteasome system and autophagy pathways facilitates protein turnover, and upregulation of antioxidant enzymes genes helps mitigate oxidative damage, while a rewired post-transcriptional regulation that increases spliceosome activity and alternative splicing frequency--each trend validated at the protein level. Concurrently, the methyltransferases responsible for DNA N6-adenine methylation (6mA), with homologous genes of AMT1 and AMT6/7 significantly downregulated. These results suggesting a multilayered regulation of ciliate encystment and the first integrated evidence that alternative splicing modulates dormancy. Our findings establish the first multi-omics framework for O. granulifera encystment, offering baseline data and tentative clues to the dormancy mechanism that will inform future inquiries into how single-celled eukaryotes endure adverse environments. IMPORTANCEOxytricha species are widely distributed in freshwater and terrestrial ecosystems, playing significant ecological roles in microbial communities. Their ability to undergo encystment provides a powerful model for studying cellular differentiation and stress adaptation in microbial eukaryotes. This study presents the first multi-omics analysis of encystment in Oxytricha granulifera, revealing microbial survival strategies through enhanced protein turnover, autophagy, alternative splicing, and DNA methylation reprogramming. These findings offer fundamental insights into dormancy mechanisms and environmental adaptation in protists, advancing our understanding of microbial resilience, evolutionary innovation, and ecological success in fluctuating environments.

genomics↗

bioRxiv2025

Siglec-F Protects Against Elastase-induced Lung Inflammation and Emphysema in Mice

Respiratory surfaces are exposed daily to billions of inhaled particles that could cause injury to alveolar tissues where gas exchange occurs. Accordingly, robust defense is essential but must involve minimal physiologic disruption. Airspace macrophages (AMs) protect lung surfaces while also maintaining tissue integrity through non-inflammatory homeostatic responses in health. However, in chronic obstructive pulmonary disease (COPD), AMs contribute to emphysematous alveolar destruction through mechanisms that are poorly understood. We hypothesized that damaging effects of AMs in emphysema result from loss of mechanisms that normally restrain homeostatic AMs. We found that Siglec-F, a common marker of AMs, exerts suppressive effects on tissue resident AMs (RAMs), thereby supporting alveolar integrity in mouse lungs during health and in a model of elastase-induced alveolar destruction. Siglec-F-deficient mice exhibited decreased alveolar numbers at baseline, and they had worsened alveolar damage after elastase challenge that was unexpectedly RAM-mediated. Transcriptomic profiling revealed dysregulation of key pathways involved in tissue remodeling and repair, including extracellular matrix degradation, TGF-{beta} signaling, and phagocytosis. These findings uncover previously unrecognized roles for RAMs and Siglec-F in preserving alveolar integrity. Our findings implicate RAMs and Siglecs as potential therapeutic targets for preserving alveolar integrity in health and for limiting alveolar damage in COPD.

immunology↗

bioRxiv2025

An Interactive AI Agent for Adaptive Modeling of RNA Region-Ligand Interactions via LLM-Generated Machine Learning Workflows

Precise modeling of RNA-ligand interactions is essential for understanding RNA functionality and designing RNA-targeted therapeutics. Current computational approaches largely focus on predicting discrete binding sites, limiting their applicability to complex RNA regions that may harbor multiple or diffuse ligand binding motifs. Here, we present RLAgent, an interactive agent framework designed to predict ligand interactions at the RNA region level, enabling higher-resolution and more flexible modeling than conventional site-centric approaches. RLAgent reframes the RNA-ligand prediction workflow as a dialogue-driven process. Through a natural language interface, users can interactively configure modeling preferences without writing code. A locally hosted large language model (LLM) acts as the core orchestration agent, automating all key components of the modeling pipeline, including data validation, feature encoding, model training, evaluation, and visualization. This agent-based design lowers technical barriers and enhances reproducibility, making RNA-ligand prediction more accessible for both computational and experimental researchers.

bioinformatics↗

bioRxiv2025

Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

Sickle cell disease and {beta}-thalassemia, two major {beta}-hemoglobinopathies, pose significant clinical challenges globally. Current treatments often face limitations in efficacy and tolerability. The transcription factor ZBTB7A has emerged as a promising therapeutic target for reactivating fetal hemoglobin expression. Here, we report the discovery and characterization of SH6, a small molecule non-IMiD degrader of ZBTB7A. SH6 induces fetal hemoglobin in erythroid cell lines in a CRBN and ZBTB7A-dependent manner, and it is capable of inducing fetal hemoglobin expression in healthy donor, SCD and {beta}-thalassemia patient CD34+ cell derived erythroid cells. The efficacy of SH6 is confirmed in a xenotransplantation humanized mouse model. SH6 outperforms currently available therapeutic agents in vitro, and shows synergy with hypomethylating agents. SH6 exhibits a favorable in vivo toxicity profile. Our findings establish SH6 as a promising therapeutic lead candidate for further optimization towards clinical development for treatment of sickle cell disease and {beta}-thalassemia.

cell biology↗

bioRxiv2025

Dynamics of dN/dS within recombining bacterial populations

The ratio of nonsynonymous to synonymous substitutions (dN/dS) encodes important information about the selection pressures acting on protein-coding genes. In bacterial populations, dN/dS often declines with the sequence divergence between strains, but the mechanisms responsible for this broad empirical trend are still debated. Existing models have primarily focused on de novo mutations, overlooking the older genetic variants that are continually introduced through horizontal gene transfer and recombination. Here we introduce a phenomenological model of dN/dS in recombining populations of bacteria, which allows us to disentangle the effects of recombination among pairs of closely related strains. We find that clonally inherited regions of the genome exhibit consistently higher dN/dS ratios, and that the accumulation of recombined segments can quantitatively explain the majority of the decline in dN/dS. We use these observations to re-examine models of purifying selection and adaptive reversion in human gut bacteria, and uncover evidence for widespread weak selection at a large fraction of protein coding sites. Our findings show that horizontal gene transfer can be an important factor in shaping genome-wide patterns of selective constraint, and raise new questions about the effectiveness of natural selection in complex bacterial populations.

evolutionary biology↗

bioRxiv2025

HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma, is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.

cancer biology↗

bioRxiv2025

Gut Clostridia and Gammaproteobacteria metabolize dietary linoleic acid to produce a signature of microbial polyunsaturated fatty acids and associated lipids

Unlike the well-studied gut fermentation of fibres and proteins, that of dietary lipids remains underexplored. Here, we investigated gut microbial metabolism of linoleic acid (LA), a predominant dietary fatty acid (FA), by the human gut microbiota, integrating isotopically labeled LA (ILLA), isotope tracking lipidomics, metagenomics, and pathway analyses. The findings were further validated within a dynamic gut-simulating environment using the Simulator of Human Intestinal Microbial Ecosystem (SHIME) and secondary analysis of a human dietary intervention trial. LA exposure led to a broad spectrum of lipids, including LA-derived microbial lipids and others produced as adaptive responses. These included various polyunsaturated FAs (PUFAs) like -linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid. ILLA tracing indicated that LA was primarily routed to {beta}-oxidation in several species within the class Clostridia and Gammaproteobacteria, and the intermediates likely facilitated FA synthesis. Temporal patterns revealed that Clostridia (e.g., Enterocloster spp.) and Pseudomonas aeruginosa dominated early-stage LA metabolism, while Gammaproteobacteria (e.g., Klebsiella spp.) played later roles, producing overlapping lipids that primarily relied on de novo FA synthesis. The SHIME confirmed LA bioprocessing over the long term and indicated that a high protein-to-fibre feeding increased PUFA concentration in the colonic condition through its stimulating effects on Gammaproteobacteria. The effect of high protein-to-fibre ratio diet on gut microbial PUFA production was confirmed by the results of the human trial. Overall, this study maps the microbial taxa, pathways, and microbial lipids associated with LA, expanding the knowledge of monoculture experiments and predicting how one of the most abundant FAs is utilized by the human gut microbiota. Our atlas of LA-derived microbial lipids provides a foundation for exploring bioactive microbial lipids that act either locally by exerting their bioactivity on the intestine while concomitantly modulating gut microbes, or systemically, once absorbed, and then released in the bloodstream to target different organs.

microbiology↗

bioRxiv2025

Albumin-STING Nanocomplex Reprograms HSPCs to Antitumor Neutrophils with Enhanced MHC I Antigen Presentation for Cancer Immunotherapy

Tumor-associated immunosuppressive neutrophils, termed myeloid-derived suppressor cells (MDSCs), compromise cancer immunotherapy. They can be pathologically programmed as early the hematopoietic stem and progenitor cell (HSPC) stage by suppressing interferon signaling. Reprogramming HSPCs toward antitumor neutrophils through the stimulator of interferon genes (STING) activation offers a promising therapeutic strategy. Here, we demonstrate that an albumin-STING nanoagonist (Nano ZSA-51D) reprograms HSPCs to generate antitumor neutrophils, enhancing MHC I-mediated CD8 T cell immunity. Nano ZSA-51D activates STING-interferon signaling in HSPCs, promoting their expansion and differentiation toward granulocyte-monocyte progenitors via STING-NF-{kappa}B-IL-6 signaling. It further reprograms neutrophils into CD14ICAM-1+ subset through STING-NF-{kappa}B-TNF- signaling, enhancing tumor infiltration. These neutrophils upregulate interferon signaling and MHC I antigen presentation, boosting tumor-specific CD8 T cell responses. Adoptive transfer of Nano ZSA-51D-reprogrammed neutrophils with -PD1 therapy achieves complete colon tumor remission. Our findings provide a novel strategy to reprogram HSPCs toward antitumor neutrophils and highlight the potential of early interventions at HSPC stage to rewire neutrophil fate for cancer immunotherapy.

immunology↗

bioRxiv2025

Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair

Diabetic foot ulcers (DFUs) are a debilitating diabetes complication in which mitochondrial dysfunction and oxidative stress are prominent but mechanistically unresolved features. Here, we identify the mitochondria-encoded circular RNA circMT-RNR2 as a novel modulator of mitochondrial redox homeostasis in human skin wound healing. CircMT-RNR2 is reduced in DFU patient tissue and diabetic mouse wounds, enriched in dermal fibroblasts, and localized to mitochondria. Its loss impairs fibroblast proliferation, migration, extracellular matrix production, and contraction by destabilizing the mitochondrial antioxidant protein PRDX3, leading to elevated oxidative stress, mitochondrial damage, and mitophagy. In murine and human ex vivo wound models, circMT-RNR2 knockdown delays healing, whereas overexpression accelerates repair and boosts antioxidant defenses. These findings position circMT-RNR2 as a mitochondrial guardian of skin healing and a promising therapeutic target for DFUs. One Sentence SummaryCircMT-RNR2, a mitochondria-encoded circular RNA suppressed in diabetic foot ulcers, promotes fibroblast function and maintains mitochondrial redox balance via stabilization of the antioxidant protein PRDX3, offering a promising therapeutic target for chronic wound repair.

molecular biology↗

bioRxiv2025

Claustrum-cortical reciprocal connections orchestrate allostatic responses following stress

Anxiety is an evolutionarily conserved response that supports threat detection and survival, yet dysregulated stress responses can drive its progression into pathological states. Here, we identify the claustrum (CLA) as a central hub that links acute stress responses to chronic affective dysfunction through cell-type-specific circuit dynamics. Acute social defeat stress robustly activated the CLA and induced anxiety-like behaviors in mice. Multimodal profiling revealed transcriptional and functional plasticity within CLA neurons, with Egr2-expressing excitatory and Gad2-expressing inhibitory populations exhibiting distinct adaptations to acute versus chronic stress. We further delineate a reciprocal CLA-anterior cingulate cortex (ACC) circuit that bidirectionally regulates stress responses in which glutamatergic CLAEgr2 [->] ACC projections promoted anxiety-like behaviors, whereas top-down ACC [->] CLAGad2inhibitory inputs constrained claustral output. Chronic stress induced hyperactivity in CLAGad2 inhibitory neurons and reshaped excitatory neuron dynamics, leading to increased intrinsic excitability, local circuit imbalance, and ultimately, depression-like phenotypes. These findings define a dynamic claustrum-centered circuit that governs the transition from adaptive anxiety to maladaptive affective states through balanced Egr2-Gad2 activity, and show that chronic-stress driven disruption of this excitatory-inhibitory equilibrium impairs stress coping and drives pathological behavioral outcomes. Graphic summaryAcute stress engages a claustrum (CLA)-centered network with activation of Egr2 excitatory neurons, promoting anxiety-like behaviors. Chronic stress drives CLAG142 neurons into a hyperactive state, enhancing local inhibition and suppressing excitatory output to induce depressive-like behaviors. A reciprocal CLAE7182[->]ACC feedforward and ACC[->]CLAG142 feedback circuit forms a state-dependent regulatory hub governing stress adaptation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/673892v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@75d664org.highwire.dtl.DTLVardef@4e5c31org.highwire.dtl.DTLVardef@86b5f2org.highwire.dtl.DTLVardef@135045_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Temporal and spatial variability of mudflat and mangrove foraminiferal eDNA assemblages and its implication for sea-level reconstruction

Reconstructing relative sea level (RSL) is essential for understanding coastal evolution and mitigating impacts of climate change. Foraminiferal assemblages are established proxies for past sea levels, but their composition can vary seasonally and spatially, affecting the reliability of morphological reconstructions. Environmental DNA (eDNA) enables high-resolution, non-invasive monitoring of foraminiferal communities and supports high-precision RSL reconstruction. However, the spatiotemporal stability of eDNA assemblages in (sub)tropical intertidal zones--and their influence on RSL reconstruction--remains uncertain. We conducted a two-year eDNA monitoring study at three intertidal stations of varying tidal elevation in Hong Kong, sampling during both dry and wet seasons to assess variability in mangrove and mudflat environments. Mid-mangrove eDNA communities exhibited temporal and spatial stability. In contrast, eDNA assemblages in mudflat and upper-mangrove environments, particularly among monothalamous foraminifera taxa, showed pronounced seasonal shifts primarily driven by environmental changes. Despite this variability in the upper-mangrove, eDNA-based elevation estimates in mangrove consistently aligned with observed elevations (within 95% credible intervals), demonstrating reliability of RSL reconstructions in these environments. However, samples from mudflats, especially during the wet season, exhibited an overprediction bias, reflecting their heightened sensitivity to seasonal and exogenous eDNA inputs. These findings highlight the need to account for seasonal and environmental variability in eDNA-based RSL reconstruction. Stable mangroves are optimal for transfer functions, while transitional/mudflat zones require caution due to higher variability. Our study provides guidance for foraminiferal eDNA application in complex, dynamic coastal settings.

ecology↗

bioRxiv2025

An activated wheat CCG10-NLR immune receptor forms an octameric resistosome

Nucleotide-binding and leucine-rich repeat (LRR) receptors (NLRs) are widespread intracellular immune sensors across kingdoms. In plants, the G10-type coiled-coil (CCG10)-NLRs form a distinct phylogenetic clade that remains poorly characterized. Here, we identified a gain-of-function (GOF) mutant of Wheat Autoimmunity 3 (WAI3), designated WAI3GOF, which encodes a constitutively activated CCG10-NLR protein due to an amino acid substitution. Cryo-EM structural analysis revealed that activated WAI3 assembles into a distinctive octameric resistosome. Arabidopsis RPS2, another CCG10-NLR, also forms an octamer, indicating a conserved structural property across monocot and dicot plants. The WAI3 resistosome mediates a prolonged and sustained increase in cytosolic calcium influx, facilitated by a unique channel architecture arising from its divergent CC domain configuration. Notably, this domain arrangement may be shared by many plant NLRs that lack the conserved EDVID motif in their CC domains. Our findings uncover a previously uncharacterized resistosome structure and provide insights into plant immune receptor plasticity.

plant biology↗

bioRxiv2025

Cis-delivering releasable IL-15 superagonist enhances antitumor immunity in cold tumors by invigorating preexisting CD25+CD8+ T cells

Antibody-mediated cis-delivery and trans-delivery both direct cytokines to tumors and have been extensively investigated in clinical trials. However, a comparative analysis of their differential effects on cytokine activity is still lacking. In this study, we initially verify that cis-delivery of cytokine demonstrates a markedly stronger antitumor effect than trans-delivery, but it also exhibits certain drawbacks, including severe toxicity, insufficient activation of CD25+CD8+ T cells, and enhanced stimulation of intratumoral regulatory T cells (Tregs). To further address these issues, we developed a conditionally releasable and cis-delivering IL-15 immunocytokine (termed PMIS), which can selectively release a free IL-15 superagonist within tumors rather than immobilizing IL-15 to PD-1+ Tregs, thereby potently stimulating CD25+CD8+ T cells. Mice treated with PMIS showed significantly reduced systemic toxicities while achieving notably stronger antitumor effects. Administered either alone or in combination with other therapies, PMIS exhibits great potential for inhibiting orthotopic cold tumor and its metastases. Mechanistically, the significant activation of the pre-existing intratumoral CD25+CD8+ T cells and the improved CD25+CD8/Treg ratio contribute to the enhanced antitumor response of PMIS. These findings underscore the indispensable role of CD25+CD8+ T cells in cis-delivering IL-15 and provide a promising strategy for overcoming resistance to therapies and effectively controlling advanced cold tumors.

immunology↗

bioRxiv2025

Interpretable deep generative ensemble learning for single-cell omics with Hydra

Single-cell omics enable the dissection of cellular heterogeneity, yet the high dimensionality, inherent noise, and sparsity present significant challenges. These challenges are amplified for rare cell populations, which are often difficult to annotate reliably but can be central to development and disease. As single-cell assays increasingly capture multiple molecular layers, the integrative analysis of such multimodal data further increases complexity. Here, we propose Hydra, a deep generative framework based on an ensemble of variational autoencoders for effective learning of unimodal and multimodal single-cell omics data. Hydra implements interpretable modules for capturing cell type-specific molecular signatures. The ensemble of such interpretable modules enables reproducible feature selection and robust cell type annotation, with particular effectiveness for rare populations. We benchmarked Hydra on a repertoire of 21 datasets, including unimodal and multimodal single-cell omics data. Our results demonstrate that Hydra offers comparable to superior performance to several state-of-the-art methods. Finally, we highlight the utility of Hydra in robustly annotating brain cellular subtypes and preserving disease-relevant signatures using our previously published dataset that profiles Alzheimers disease.

bioinformatics↗

bioRxiv2025

BIN1 deficiency leads to DNA damage and neuronal insulin resistance through ATM dysregulation

The major neuronal isoform of the AD risk gene BIN1 is specifically reduced in patients. In the present work, we demonstrate that BIN1 is necessary for intact insulin signaling and its loss leads to cellular-level insulin resistance. Persistently activated mTORC1 feedback inhibits the insulin signaling; meanwhile, ATM-dependent DNA Damage Response decreases the expression of multiple insulin signaling pathway members. Unexpectedly, nuclear ATM activation is accompanied by autophagic degradation of the cytoplasmic ATM, rendering neurons susceptible to oxidative stress, which predisposes oxidative DNA damage, DNA strand breaks, and ATM-dependent DNA Damage Response. Treating BIN1-deficient mice with rapamycin or liraglutide to improve the insulin response, or with the natural antioxidant alpha-lipoic acid to attenuate oxidative stress, both effectively preserved the spatial cognitive ability. Lastly, we reanalyzed a single-cell transcriptomic dataset from human neurons and identified positive correlations between levels of BIN1 and the insulin signaling, as well as neuronal activity. Together, this work revealed an ATM-centered mechanism that globally damages neuronal health in BIN1-deficient pyramidal neurons, which could be a driving force in the AD disease course.

cell biology↗

bioRxiv2025

Foxp3 and BATF cooperatively direct cis-regulatory programs and gene expression for functional differentiation of Treg cells

Mechanisms by which diverse transcription factors (TFs) shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. By investigating interactions between BATF and Foxp3 TFs, we discovered their cooperative roles in directing cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis regulatory and transcriptional landscape critical for functional Treg cell differentiation.

immunology↗

bioRxiv2025

Foraminiferal environmental DNA reveals late Holocene sea-level changes

Reconstructing past relative sea level (RSL) provides critical insight into the mechanisms driving RSL change and informs future projections. Foraminifera are widely used sea-level indicators, but their application is often limited by poor preservation. Here, we demonstrate that foraminiferal environmental DNA (eDNA) and sedimentary ancient DNA (sedaDNA) provide a complementary approach to traditional morphological methods for RSL reconstruction. By analyzing surface sediments and a core from subtropical intertidal environments in the Pearl River Delta, we found that foraminiferal eDNA and sedaDNA assemblages exhibit clear vertical zonation, consistent with morphological results. An eDNA-based transfer function enabled high-resolution RSL reconstructions with decadal temporal and decimeter vertical precision from two periods: 290-1703 CE and 1956-present. Notably, eDNA preservation extended RSL reconstruction far earlier than morphological analyses (1956 CE). The eDNA reconstruction closely matched tide-gauge and geological RSL records, underscoring its potential as a robust tool for reconstructing past RSL and its driving mechanisms.

paleontology↗