Biology subjects

Yang, H.

Publications and source records attributed to Yang, H..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

eyeris: A flexible, extensible, and reproducible pupillometry preprocessing framework in R

Pupillometry provides a non-invasive window into the mind and brain, particularly as a psychophysiological readout of autonomic and cognitive processes like arousal, attention, stress, and emotional states. Pupillometry research lacks a robust, standardized framework for data preprocessing, whereas in functional magnetic resonance imaging and electroencephalography, researchers have converged on tools such as fMRIPrep, EEGLAB and MNE-Python. Many established pupillometry preprocessing packages and workflows fall short of serving the goal of enhancing reproducibility, especially since most existing solutions lack designs based on Findability, Accessibility, Interoperability, and Reusability (FAIR) principles. To promote FAIR and open science practices for pupillometry research, we developed eyeris, a complete pupillometry preprocessing suite designed to be intuitive, modular, performant, and extensible (https://github.com/shawntz/eyeris). Out-of-the-box, eyeris provides a recommended preprocessing workflow and considers signal processing best practices for tonic and phasic pupillometry. Moreover, eyeris further enables open and reproducible science workflows, as well as quality control workflows by following a well-established file management schema and generating interactive output reports for both record keeping/sharing and quality assurance of preprocessed pupil data prior to formal analysis. Taken together, eyeris provides a robust all-in-one transparent and adaptive solution for high-fidelity pupillometry preprocessing with the aim of further improving reproducibility in pupillometry research.

neuroscience↗

bioRxiv2025

Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications

A deeper understanding of sickle cell disease (SCD) pathophysiology is critical for identifying novel therapeutic targets. A hallmark of SCD is abnormal phosphatidylserine (PS) exposure on sickle red blood cells (RBCs), which contributes to anemia, thrombosis, and vaso-occlusive crises (VOC). However, the mechanisms underlying this excessive PS exposure remain unclear. Here, we identify TMEM16F, a Ca2+-activated lipid scramblase, as a key mediator of PS exposure downstream of Ca2+ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging and flow cytometry reveal that deoxygenation-induced sickling promotes PIEZO1 activation, triggering Ca2+ entry, TMEM16F activation, and PS exposure. This cascade enhances PS+ microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti-gout drug, suppresses these changes. Our findings thus define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso-occlusion associated with SCD. Brief SummaryEnhanced PIEZO1 activation in sickle red blood cells promotes TMEM16F scramblase-mediated phosphatidylserine exposure and subsequent sickle cell disease complications. Disrupting this coupling presents a potential therapeutic strategy.

physiology↗

bioRxiv2025

SARS-CoV-2 Nonstructural Protein 3 Remodels the Phosphorylation of Target Proteins via Protein-Protein Interactions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), triggered a global pandemic with a significant impact on human health. The molecular basis of its pathogenicity remains incompletely understood. The viral nucleocapsid (N) protein, the most abundant protein expressed during SARS-CoV-2 infection, is thought to contribute to disease progression. Yet, its interaction network in the context of viral infection remains largely unexplored. Here, we generated a recombinant (r)SARS-CoV-2 expressing a Strep-tagged N protein by using a reverse genetics system. Affinity purification and mass spectrometry identified an interaction between SARS-CoV-2 N protein and the nonstructural protein 3 (NSP3). Domain mapping revealed that the N dimerization domain and the N-terminal region of NSP3 mediate this interaction. Notably, an N protein mutant lacking its N-terminal domain exhibited enhanced binding to NSP3 and underwent dephosphorylation, implicating NSP3 as a potential viral phosphatase. We further found that NSP3 interacts with Interferon Regulatory Factor 3 (IRF3), a key transcription factor involved in host type I interferon (IFN-/{beta}) antiviral response. SARS-CoV-2 NSP3 expression suppressed poly(I:C)-induced IRF3 phosphorylation and broadly reduced cellular phosphorylation levels in a dose-dependent manner. These findings suggest that SARS-CoV-2 NSP3 modulates host phosphorylation dynamics to subvert antiviral signaling and facilitate viral replication. SIGNIFICANCEUnderstanding virus-host and virus-virus interactions is essential for elucidating the mechanisms of viral replication and immune evasion. Previous studies using individually expressed SARS-CoV-2 proteins have identified host interacting factors but have largely overlooked interactions between viral proteins. Here, we engineered a recombinant SARS-CoV-2 virus expressing Strep-tagged nucleocapsid (N) protein, allowing the identification of both viral and host proteins interacting with N during live infection. We discovered an interaction between N and nonstructural protein 3 (NSP3), revealing a previously unrecognized role for NSP3 in modulating protein phosphorylation, interacting with Interferon Regulatory Factor 3 (IRF3), and regulating the innate immune response. This work demonstrates a powerful strategy for dissecting protein interaction networks during SARS-CoV-2 infection and identifies potential targets for therapeutic intervention.

microbiology↗

bioRxiv2025

The Mycobacterium tuberculosis ESX effector promotes pyroptosis-dependent pathogenicity and dissemination

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/653593v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@8cd5e5org.highwire.dtl.DTLVardef@2ec22forg.highwire.dtl.DTLVardef@1ceb773org.highwire.dtl.DTLVardef@6dfba4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG Mycobacterium tuberculosis (Mtb) remains a major global health threat, partly due to the extensive cytotoxicity induced during infection. Although GSDMD-mediated excessive pyroptosis promotes pathogen dissemination and tissue damage in tuberculosis, the mechanism remains poorly understood. Here, we identify the effector EccB5, a component of the Mtb ESX-5 secretion system, as a key driver of pyroptosis and hyperinflammatory responses. EccB5 enhances Mtb virulence by inducing pyroptosis of macrophages, promoting bacterial dissemination and exacerbating lung pathology. Conditional knockdown EccB5 increases host cell viability. Mechanistically, EccB5 directly interacts with GSDMD, strengthens its association with caspase-1, and facilitates caspase-1-mediated cleavage of GSDMD both in vitro and in vivo. In summary, our findings uncover a precise mechanism by which Mtb modulates host responses and advances its pathogenicity.

microbiology↗

bioRxiv2025

A computational framework for mapping isoform landscape and regulatory mechanisms from spatial transcriptomics data

Transcript diversity including splicing and alternative 3 end usage is crucial for cellular identity and adaptation, yet its spatial coordination remains poorly understood. Here, we present SPLISOSM (SpatiaL ISOform Statistical Modeling), a computational framework for detecting isoform-resolution patterns from spatial transcriptomics data. SPLISOSM leverages multivariate testing to account for spot- and isoform-level dependencies, demonstrating robust and theoretically grounded performance on sparse data. In the mouse brain, we identify over 1,000 spatially variable transcript diversity events, primarily in synaptic signaling pathways linked to neuropsychiatric disorders, and uncover both known and novel regulatory relationships with region-specific RNA binding proteins. We further show that these patterns are evolutionarily conserved between mouse and human prefrontal cortex. Analysis of human glioblastoma highlights pervasive transcript diversity in antigen presentation and adhesion genes associated with specific microenvironmental conditions. Together, we present a comprehensive spatial splicing analysis in the brain under normal and neoplastic conditions.

bioinformatics↗

bioRxiv2025

Plastic-elastomer heterostructure for robust flexible brain-computer interfaces

Electronics for neural signal recording must be robust across multiple and deep brain regions while preserving tissue-level flexibility to ensure stable tracking over months or years. However, existing electronics cannot simultaneously achieve robustness and tissue-level flexibility, limiting their potential for customizable and scalable neuroscience research and clinical applications. Here, we introduce FlexiSoft, an electronic platform based on a plastic-elastomer heterostructure that uniquely integrates mechanical robustness and tissue-level flexibility. Compared to conventional flexible electronics of similar thickness, the FlexiSoft platform demonstrates an order-of- magnitude improvement in both mechanical robustness (critical energy release rate) and flexibility (flexural rigidity). Leveraging these mechanical advantages, we developed FlexiSoft probe for robust implantation, demonstrated by its ability to withstand repeated insertion and removal, as well as to reach centimeter-scale depths comparable to those in the human brain. The platform enables long-term recording from the same neurons across the hippocampus (HPC) and primary motor cortex (M1) during a months-long motor learning task, thereby revealing long-term dynamic changes in neuronal firing patterns. Additionally, FlexiSofts unique robustness and flexibility enable curved implantation routes, opening new directions of customizable implantation pathways. In summary, we present FlexiSoft as a novel, robust, and tissue-level flexible heterostructure electronics platform that advances flexible brain-computer interfaces (BCIs) with strong translational potential for neuroscience and clinical applications.

bioengineering↗

bioRxiv2025

Pervasive phenotypic effects of Fbxo42 controlled by regulation of PP4 phosphatase

F-box proteins are the substrate recognition modules of the SCF (SKP1-Cullin- F-box) E3 ubiquitin ligase complex. FBXO42, an understudied member of this family, has recently emerged as a modulator of key cellular processes, including cell cycle progression, DNA damage response and glioma stem cell survival. In this study, we define the function of FBXO42 as a major regulator of the protein phosphatase PP4. Phosphoprotein phosphatases (PPPs) have a broad array of substrates, hence necessitating tight regulation. We observe that FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits with the net effect of restraining the latters phosphatase activity. FBXO42 depletion unleashes PP4 activity with broad cellular effects highlighting FBXO42 as a novel regulatory node in ubiquitin-mediated signalling for future therapeutic exploitation. Impact StatementFBXO42 is a major regulator of PP4 phosphatase impacting multiple cellular phenotypes.

biochemistry↗

bioRxiv2025

A real-time detection and non-destructive warning method for zebrafish body surface anomalies based on improved YOLOv8 framework

The detection of anomalies on fish surfaces is of critical importance for assessing fish health status, preventing fish disease outbreaks, predicting changes in water quality, enhancing fish welfare. The zebrafish (Danio rerio), a key model organism, has been increasingly utilized in various fields, including medicine, genetics and environmental toxicology. This has led to a corresponding increase in demand for intelligent management and detection systems. However, traditional methods of fish disease detection may have irreversible effects on fish, particularly small species, and often fail to meet the precision, non-destructive warning, and real-time requirements for zebrafish detection. To address this issue, this study proposes a novel method based on the YOLOv8 framework, designated ESC-YOLOv8-seg. This method significantly enhances the precision and speed of detecting surface abnormalities on small fish in complex settings by integrating the EMA the SPPELAN and C2f-Faster modules, and adding a detection head tailored for small targets. Furthermore, the integration of positional information and surface features enables the method to achieve real-time monitoring and non-destructive early warning of fish surface abnormalities. The proposed method enhances precision in small target detection and achieves high accuracy in discerning subtle differences among detection targets. In real aquaculture settings, it can reach an average speed of 106 FPS with a detection accuracy of 98%. Although this study has been designed to meet the specific needs of zebrafish scientific research, it is highly generalisable and can be applied to the real-time detection of underwater surface abnormalities in a range of fish species in aquaculture.

bioinformatics↗

bioRxiv2025

From Fragmentation to Resolution: High-Fidelity Genome Assembly of Zancudomyces culisetae through Comparative Insights from PacBio, Nanopore, and Illumina Sequencing

Zancudomyces culisetae is an obligate symbiotic fungus inhabiting the digestive tracts of aquatic insect larvae, including black flies, midges, and mosquitoes. With a global distribution and high prevalence in disease-transmitting insects, Z. culisetae serves as a model for studying insect gut fungi. A previous draft genome assembly using Illumina short reads provided insights into its genome composition, such as a low GC ratio and evidence of horizontal gene transfer. However, its fragmented nature has limited deeper exploration of the evolutionary mechanisms shaping these gut symbionts. To address this gap, we generated a wealth of genomic resources for Z. culisetae using multiple sequencing platforms, including Illumina, Oxford Nanopore, PacBio-CLR (Complete Long Reads), and PacBio-HiFi (High Fidelity). This also provides an opportunity to compare these popular sequencing methods to suggest the optimal approach for fungal genome assembly. Our results suggest that PacBio-HiFi produced the most complete assembly, yielding a 27.8 Mb genome size with 26 contigs, representing the highest-quality genome of insect gut fungi to date. Additionally, we generated transcriptomic data to support genome annotation, identifying 8,484 protein-coding genes. Despite the improved genome quality, Z. culisetae lacks approximately 20% of Benchmarking Universal Single-Copy Orthologue (BUSCO) commonly found in fungi, reflecting adaptations to its obligate symbiotic lifestyle. This study not only provides valuable genomic resources for insect gut fungal research but also evaluates the strengths and limitations of current genome sequencing and assembly approaches, offering best practices for fungal genome analysis and genetic research. Article SummaryMosquito larvae harbor gut-dwelling fungi that may influence their development and disease transmission. Zancudomyces culisetae is a widespread fungal symbiont of mosquitoes, but its genome remained incomplete. This study explored and compared popular sequencing technologies, including Illumina, Oxford Nanopore, PacBio-CLR, and PacBio-HiFi, to generate a high-quality genome, alongside the first transcriptomic data. PacBio-HiFi produced the most complete assembly (27.8 Mb, 26 contigs) with 8,484 protein-coding genes, though [~]20% of core fungal genes were absent, reflecting symbiotic adaptation. This study establishes a genomic foundation for insect gut-dwelling fungi and evaluates available sequencing and assembly strategies for high-quality fungal genome production.

genomics↗

bioRxiv2025

RBMX2: A Pivotal Regulator Linking Mycobacterium bovis Infection to Epithelial-Mesenchymal Transition and Lung Cancer Progression

Tuberculosis (TB) is a complex disease that arises from the dynamic interplay among the pathogen, host, and environmental factors. In 2022, TB affected approximately 10.6 million people worldwide, resulting in 1.3 million deaths. In regions with a high burden of zoonotic TB, Mycobacterium bovis (M. bovis) accounts for nearly 10% of human TB cases. The immune evasion strategies and latent nature of Mycobacterium tuberculosis (M. tb) pose significant challenges to understanding the host immune response to TB infection. In this study, we identify RNA-binding motif protein X-linked 2 (RBMX2) as a novel host factor that may facilitate M. bovis infection. However, the molecular mechanisms and functional roles of RBMX2 during M. bovis infection remain poorly understood. Our findings show that RBMX2 is significantly upregulated across multiple cell types following infection, including embryonic bovine lung (EBL) cells, bovine macrophage (BoMac) cells, bovine pulmonary alveolar primary cells, and human alveolar epithelial cells (A549). Using a combination of global transcriptomic sequencing, proteomic profiling, cell adhesion assays, ChIP-PCR, and Western blotting, we demonstrate that RBMX2 suppresses cell adhesion and tight junction formation in EBL cells while promoting M. bovis adhesion and invasion through activation of the p65 signaling pathway. Importantly, integrated analyses of transcriptomic, proteomic, and metabolomic data reveal that RBMX2 plays a key role in regulating epithelial-mesenchymal transition (EMT), a cellular process closely associated with cancer progression. To further explore the potential link between RBMX2 and cancer, we analyzed the TIMER2.0 database and found elevated RBMX2 expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared to normal lung tissues. These findings were corroborated by immunofluorescence staining. Using an M. bovis-infected BoMac-induced EBL-EMT model, we show that RBMX2 promotes EMT through activation of the p65/MMP-9 pathway following infection. Additionally, we validated the EMT process in human lung epithelial cancer cells (H1299), further supporting the involvement of RBMX2 in this transition. Collectively, our study identifies RBMX2 as a novel host factor that may enhance M. bovis infection and drive infection-induced EMT. These findings provide new insights into the molecular mechanisms underlying TB pathogenesis and suggest that RBMX2 could serve as a potential target for the development of TB vaccines and therapeutic strategies against TB-associated lung cancer.

microbiology↗

bioRxiv2025

The piRNA PETPIR Regulates Trophoblast Function by Modulating YTHDF2-Mediated m6A Methylation of NDRG1 in Preeclampsia

Preeclampsia is marked by abnormal placental development and impaired trophoblast function. We identified Preeclampsia-associated trophoblast piRNA (PETPIR) as an important regulator of trophoblast function and m6A modifications. Placental samples from preeclamptic and healthy pregnancies were analyzed using piRNA microarrays and m6A epitranscriptomic profiling. Functional assays in trophoblast cells, transcriptomic analysis, and an in vivo PETPIR-overexpressing mouse model were employed to investigate PETPIRs mechanistic roles. We found that PETPIR was significantly upregulated in preeclamptic placentas. PETPIR inhibited trophoblast cell proliferation, migration, and invasion by inducing cell cycle arrest and apoptosis. Transcriptome analysis demonstrated that PETPIR activated hypoxia-responsive pathways. Additionally, PETPIR enhanced global m6A methylation and stabilized NDRG1 transcripts by interacting with the m6A reader YTHDF2. In vivo, PETPIR overexpression in pregnant mice recapitulated key features of preeclampsia, including maternal hypertension and fetal growth restriction. These results suggest PETPIR is a key player in the pathogenesis of preeclampsia, functioning through the PETPIR/YTHDF2/NDRG1 axis to drive hypoxia and m6A epitranscriptomic dysregulation. We provide novel insights into preeclampsias molecular mechanisms, highlighting piRNA as a promising biomarker and therapeutic target.

molecular biology↗

bioRxiv2025

PIEZO1 Drives Trophoblast Fusion and Placental Development

PIEZO1, a mechanosensor1,2 in endothelial cells, plays a critical role in fetal vascular development during embryogenesis3,4. However, its expression and function in placental trophoblasts remain unexplored. Here, we demonstrate that PIEZO1 is expressed in placental villus trophoblasts, where it is essential for trophoblast fusion and placental development. Mice with trophoblast-specific PIEZO1 knockout exhibit embryonic lethality without obvious vascular defects. Instead, PIEZO1 deficiency disrupts the formation of the syncytiotrophoblast layer in the placenta. Mechanistically, PIEZO1-mediated calcium influx activates TMEM16F lipid scramblase, facilitating the externalization of phosphatidylserine, a key "fuse-me" signal for trophoblast fusion5,6. These findings reveal PIEZO1 as a crucial mechanosensor in trophoblasts and highlight its indispensable role in trophoblast fusion and placental development, expanding our understanding of PIEZO1s functions beyond endothelial cells during pregnancy.

cell biology↗

bioRxiv2025

A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death

Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkins lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.

cancer biology↗

bioRxiv2025

ARIH1 deficiency impairs spatial learning and memory via GIRK2 upregulation in hippocampal CaMKII-expressing neurons in mice

Alterations of Ariadne RBR E3 Ubiquitin Protein Ligase 1 (ARIH1), a human homologue of Drosophila Ari, have been associated with a number of human diseases. Given the importance of ubiquitin-proteasome system in learning and memory, whether ARIH1 involves in the process has not been explored. Here we report that ARIH1-deficent mice exhibited a defect in learning and memory evidenced in Morris water maze and in novel object recognition tests without changes in basal motor activity, anxiety, and depressive behaviors. We found that ARIH1 deficiency resulted in an upregulation of G protein-gated inwardly rectifying potassium channel 2 (GIRK2) in dorsal hippocampus that was attributed to the impaired ubiquitination and degradation. Locally injection of ARIH1-expressing lentivirus to restore the ARIH1 expression of dorsal hippocampus in ARIH1+/- mice restored the impaired learning and memory. Moreover, selective knockdown ARIH1 in dorsal hippocampal calcium-calmodulin-dependent protein kinase II (CaMKII)-expressing neurons, but not for parvalbumin+ (PV) or somatostatin+ (SST) neurons, in naive mice was sufficient to mimic the damage in learning and memory of ARIH1+/- mice. Lastly, we demonstrated that systemically or locally inhibition of GIRK activity was able to improve ARIH1 deficiency-induced decline of learning and memory in ARIH1+/- mice. The present study discovered the clear role of ARIH1 in mediating learning and memory, defect of ARIH1 resulted in upregulation of GIRK2 in hippocampal CaMKII-expressing neurons via modulating the ubiquitination and degradation GIRK2.

neuroscience↗

bioRxiv2025

A Priming Circuit Controls the Olfactory Response and Memory in Drosophila

Priming is a process by which exposure to a stimulus affects the response to a subsequent stimulus in humans. In this study we found that in Drosophila, a prior encounter with an aversive stimulus results in enhanced preference for a following novel odor, while an appetitive stimulus leads to reduced preference for a new odor. This priming behavior of flies relies on the well-studied olfactory memory circuits including Kenyon cells (KC), dopaminergic neurons (DANs), and mushroom body output neurons (MBONs). Aversive stimulus results in increased odor responses in reward DANs that innervate the {gamma}4 lobe of the mushroom body (MB) and decreased odor responses in a {gamma}4{gamma}5-innvervating repulsive MBON. We concluded that these neurons are required for the priming effects in flies. These results characterized the newly found priming behavior in flies and demonstrated the sheer influence of unconditioned stimulus on odor perception during associative learning.

neuroscience↗

bioRxiv2025

Metabolically purified human stem cell-derived hepatocytes reveal distinct effects of Ebola and Lassa viruses

Ebola and Lassa viruses require biosafety-level-4 (BSL4) containment, infect the liver, and cause deadly hemorrhagic fevers. The cellular effects of these viruses, and whether different families of hemorrhagic-fever viruses elicit similar effects, remain fundamental questions in BSL4 virology. Here, we introduce a new metabolic selection approach to create nearly-pure hepatocytes from human pluripotent stem cells, killing non-liver cells by withholding essential nutrients. Unexpectedly, Ebola and Lassa exerted starkly different effects on human hepatocytes. Ebola infection activated the integrated stress response (ISR) and WNT pathways in hepatocytes in vitro and killed them, whereas Lassa did not. Within non-human primates, Ebola likewise infected hepatocytes and activated ISR signaling in vivo. In summary, we present a single-cell transcriptional and chromatin accessibility roadmap of human hepatocyte differentiation, purification, and viral infection.

cell biology↗

bioRxiv2025

Collective Transitions from Orbiting to Matrix Invasion in 3D Multicellular Spheroids

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in "mosaic" spheroids, showing a small fraction of "leader" cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

biophysics↗

bioRxiv2025

De-novo DNA Methylation of Bivalent Promoters Induces Gene Activation through PRC2 Displacement

Promoter DNA methylation is a key epigenetic mark, commonly associated with gene silencing. However, we noticed that a positive association between promoter DNA methylation and expression is surprisingly common in cancer. Here, we use hit-and-run CRISPR/dCas9 epigenome editing to evaluate how deposition of DNA methylation can regulate gene expression dependent on pre-existing chromatin environment. While the predominant effect of DNA methylation in non-bivalent promoters is gene repression, we show that in bivalent promoters this often leads to gene activation. We demonstrate that gain of DNA methylation leads to reduced MTF2 binding and eviction of H3K27me3, a repressive mark that guards bivalent genes against activation. Our cancer patient data analyses reveal that in cancer, this mechanism likely leads to activation of a large group of transcription factors regulating pluripotency, apoptosis, and senescence signalling. In conclusion, our study uncovers an activating role of DNA methylation in bivalent promoters, with broad implications for cancer and development.

genomics↗