Biology subjects

Ye, F.

Publications and source records attributed to Ye, F..

At least 19 recordsLinked to original sources

bioRxiv2026

scGSCA: gene-set differential co-expression analysis for single-cell RNA sequencing data

Understanding disease-associated pathway coordination requires distinguishing phenotype-related co-expression changes from differences across cellular contexts while accounting for cells sampled from the same subject. Bulk gene-set co-expression methods do not directly address the sparse counts, single-cell distributional noise, subject-level dependence, and cell-type heterogeneity of single-cell RNA sequencing (scRNA-seq) data. We developed single-cell gene-set co-expression analysis (scGSCA), a framework for pathway-level differential co-expression analysis in scRNA-seq data. scGSCA fits gene-wise zero-inflated negative binomial mixed models with subject-level random effects and computes gene-set co-expression statistics from quantile residual correlations. It provides an overall differential gene-set co-expression analysis and an interaction test to assess whether the co-expression pattern between two cell types varies by sample phenotype. We applied scGSCA to tumor-normal gastric, breast-subtype, and lung-skin comparisons with matched bulk and scRNA-seq data. The overall test identified signals not captured in bulk analysis, including Axon guidance in gastric cancer and estrogen-response, IL6-JAK-STAT3, and TNF/NF-{kappa}B pathways in breast cancer. The interaction test further identified co-expression contrasts across cell types. scGSCA extends gene-set co-expression analysis to single-cell data while retaining subject-level structure and cell-type-specific context. scGSCA is freely available as an open-source R package.

bioinformatics↗

bioRxiv2026

A mechanism-annotated benchmark reveals limited fidelity to drug-response signatures in single-cell perturbation models

Single-cell drug perturbation models are increasingly used to predict how compounds remodel cellular states, but they are still largely assessed by expression reconstruction. Whether high expression similarity reflects preservation of drug-response signatures remains unclear. Here we present scDrugPerturb-Bench, a mechanism-annotated benchmark that links matched control and drug-treated single-cell RNA-sequencing profiles to literature-curated directional key-gene evidence. The resource covers 181 datasets, 423 annotated response cases, 717 unique key genes and 2.5 million cells. We introduce the Mechanism Fidelity Score (MFS) to evaluate key-gene direction, effect-size recovery, gene-set coherence, mechanism specificity and pathway-level response polarity. Across 12 perturbation-prediction models, 3 baselines and 10 data splits, expression-similarity metrics were weakly aligned with MFS and selected different model configurations. Mechanism-aware selection improved early drug retrieval in a transcriptome-based drug design evaluation, indicating that MFS provides practical information beyond benchmark reporting. Systematic benchmarking revealed limited fidelity to drug-response signatures across cell-line and source-integrated settings. Frozen single-cell foundation model embeddings produced local, metric-dependent gains rather than universal improvements, and source context substantially reshaped model assessment. Hard-negative tests further showed that plausible perturbation responses can arise from non-specific transcriptional shortcuts. These results show that expression reconstruction is an insufficient proxy for preserving drug-response signatures and establish scDrugPerturb-Bench as a benchmark for mechanism-aware evaluation of single-cell drug perturbation models.

bioinformatics↗

bioRxiv2026

Whole-genome resequencing-based comparative variant analysis identifies candidate genes associated with cross-beak phenotype in Huiyang Bearded chickens

Cross-beaks are deemed a threat to poultry health, productivity, and animal welfare. Nevertheless, due to sporadic cases, heterogeneity of gene loci and incomplete dominance, the molecular mechanism of cross-beak formation, especially the degree of cross, is not yet clear. Thus, we screen key genes and reveal the possible phenotypic formation mechanism of cross-beak by comparison with different degrees of deformity in Huiyang Bearded chickens by compare whole-genome resequencing-based variant analysis. Comparative analysis between cross-beak and normal-beaked chickens identified differential variants in several candidate genes, including CDH11, CTNNAL1, NRXN3, NRXN1, CDH5, SDC3, and DHFR. Genes harboring these variants were enriched in pathways related to cell adhesion molecules and metabolic processes, with functional annotations involving cell-cell adhesion and neural crest cell migration. Comparative analysis between chickens with severe and slight cross-beak deformities identified additional candidate genes, including MRPL21, NSUN2, DDX55, GNB3, and NFKB2. These genes were associated with enriched terms and pathways related to focal adhesion, amyotrophic lateral sclerosis, steroid 7 -hydroxylase activity, and skin-barrier establishment. These findings provide a preliminary catalogue of genetic variants and candidate genes for future functional studies of cross-beak development and severity in chickens.

genomics↗

bioRxiv2026

Transcriptional Mapping of Neuro-Immune Interactions during Homeostasis and HIV infection using Microglia-containing Human Cerebral Assembloids

BackgroundA significant number of people with HIV-1 still experience neurocognitive impairments (NCI), despite effective antiretroviral treatment. HIV-NCI is diverse and multifactorial, with mechanisms that cause its development and progression still not fully understood. We examined early HIV-related changes in brain stability and studied neuroimmune interactions at the single-cell level to better understand how NCI develops. MethodsTo model changes in brain homeostasis, we developed an advanced human iPSC-derived 3D cerebral assembloid model that includes microglia, by co-developing neural progenitor cells with tdTomato-tagged and CD34+ cell-derived microglial precursors. Assembloids were infected with a macrophage R5-tropic HIV-1 strain NL-AD8. Viral spread was measured using a proviral DNA assay, qPCR for HIV RNA, and 3D immunostaining for Tat protein. Single-cell transcriptomics with tdTomato lineage tracing revealed HIV-1 induced disturbances and cell-type-specific responses. The niche net algorithm was used to identify ligand-receptor interactions between microglia and the brain microenvironment during homeostasis and HIV infection. ResultsHighly ramified tdTomato+ IBA-1+ microglia were evenly distributed throughout the assembloids within 15 days of culture. Single-cell transcriptomics identified microglia, excitatory/inhibitory neurons, astrocytes, and oligodendrocyte precursors within the assembloids. Neurons in microglia-containing assembloids upregulated genes related to neurotransmission, synaptogenesis, and neuronal development compared to neurons in organoids without microglia. Niche net analysis showed microglia-derived neurotropic ligands supported neuronal and astrocytic differentiation. The R5-tropic HIV-1 specifically targeted microglia, inducing a reactive phenotype that transmitted interferon and pro-inflammatory signals to nearby cells and increased MHC-I antigen-presentation genes. Notably, neuroprotective ligands from non-glial cells and bystander microglia in the assembloids attempted to counteract HIV-related inflammation and promote neural repair. ConclusionsOur microglia-containing assembloid model replicates in vivo neurodevelopmental interactions, allowing high-resolution analysis of homeostatic and HIV-induced responses across different brain cell types. Homeostatic microglia support neuronal health, while HIV infection triggers a reactive state that spreads inflammatory signals within the brain environment. The presence of multiple glial and non-glial populations uncovered previously unknown crosstalk, including bystander microglial phenotypes and neuroprotective signaling mechanisms that counteract inflammation. These findings emphasize early HIV responses that balance injury and adaptation, offering insights for developing therapies that target microglial activation, boost neuroprotection, and address HIV reservoirs in the brain.

microbiology↗

bioRxiv2026

Single-nuclear RNA sequencing reveals an ATF3-independent sensory-neuron program after surgical incision

BackgroundAcute postoperative pain is common and often treated with opioids, but which sensory-neuron changes are responsible for the peripheral drive of pain is poorly defined. Skin incision induces activating transcription factor 3 (ATF3), the canonical marker of nerve injury, in dorsal root ganglion (DRG) neurons, and ATF3 marks the neurons that remain hyperexcitable. Whether ATF3 is required for postoperative pain is unknown. MethodsAdult mice of both sexes underwent hind-paw plantar incision. Postoperative nociceptive behavior was compared between sensory-neuron-specific ATF3 conditional-knockout mice (AvilCre/+; Atf3fl/fl) and littermate controls using assays that probe distinct primary-afferent modalities (von Frey; Hargreaves; dynamic light touch) together with an operator-independent index of spontaneous injury behavior. Single-nucleus RNA sequencing of wild-type and ATF3-null DRG sensory neurons (naive and postoperative day 1) characterized the initiating injury program; transcription-factor-activity inference, RNAscope, and phospho-c-Jun immunostaining examined c-Jun; and the oral dual leucine zipper kinase (DLK) inhibitor GNE-3511, given at the time of incision, was tested behaviorally. ResultsIncision transiently induced ATF3 in a subset of DRG neurons, returning to baseline by day 14, in parallel with the two-week course of nociceptive behavior. Deleting ATF3 in sensory neurons did not change the onset or resolution of nociceptive behavior on any readout, in either sex, across mechanical, thermal, and tactile modalities. Single-nucleus profiling showed a broad surgery-responsive nociceptor program in which ATF3 was the most strongly induced gene, yet only 23% of surgery-responsive neurons expressed it. Without ATF3, the program was remodeled but not abolished, and transcription-factor-activity inference nominated c-Jun as a candidate ATF3-independent factor; incision induced c-Jun in vivo. Systemic inhibition of DLK, which activates c-Jun pathway, lowered c-Jun phosphorylation and reduced evoked nociceptive hypersensitivity. ConclusionsOur results indicate that ATF3 marks part of the injured sensory neuron but does not drive acute post-surgical nociceptive behavior, and that it is not required for the postsurgical pain behaviors across afferent modalities carried by molecularly distinct nociceptor classes. The underlying injury program is broader than ATF3 and is nominated to depend on c-Jun. Because DLK inhibition, given at the time of incision, reduced evoked hypersensitivity, we propose the DLK-JNK-c-Jun axis as a candidate perioperative non-opioid target, which will require further genetic validation.

neuroscience↗

bioRxiv2026

Resting fMRI functional connectivity reflects fluctuations in inhibitory interneuron activity

Primate brain function relies on distributed cortical networks. These networks are commonly identified through fMRI functional connectivity, defined as the spatial correlation of hemodynamic fluctuations measured at rest. To assess the contribution of distinct neuronal populations to fMRI functional connectivity, we obtained concurrent fMRI and dense single-unit recordings at rest in the macaque. Then, using standard waveform-based classification of action potential shape, we compared the activity of different neural subtypes to the local and brain-wide patterns of fMRI activity. Putative excitatory neurons were functionally intermixed, with approximately half having positive and half negative correlation with the local fMRI signal. By contrast, all putative inhibitory interneurons were positively correlated, with one subclass exhibiting brain-wide correlation that closely matched conventional seed-based functional connectivity. These findings indicate that, although excitatory projection neurons may underpin long-range network communication interneuron activity most closely matches the fMRI fluctuations at the heart of resting functional connectivity.

neuroscience↗

bioRxiv2026

Vitamin D3 attenuates nitrogen mustard-induced dermal toxicity by enhancing microbial butyrate production via the intestinal VDR-α-defensin signaling pathway

Nitrogen mustard (NM)-caused severe cutaneous damage lacks effective targeted therapies. Vitamin D3 (VD3) shows promise as a therapy for NM-induced dermal toxicity; however, the underlying mechanisms remain elusive. Herein, we initially confirmed that NM induced gut flora dysbiosis, characterized by a decrease of Akkermansia muciniphila (AKK) abundance, thereby leading to butyrate reduction. Antibiotics (ABX) significantly promoted NM-induced skin injury, whereas fecal microbiota transplantation of the controls feces (HC-FMT) or AKK administration attenuated NM-induced dermal toxicity. HC-FMT or AKK significantly increased butyrate levels in feces and serum of NM-treated mice. Butyrate notably attenuated ABX-caused acceleration of NM-induced skin injury. Meanwhile, NM markedly decreased the expression of -defensins, MMP7, and VDR. NM failed to further decrease AKK abundance and BA contents in intestinal MMP7-deficient mice, which was abolished by human alpha defensin 5 (HD5) overexpression. And intestinal MMP7 deficiency enhanced NM-caused skin injury, which was markedly attenuated by HD5 overexpression, AKK transplantation, or BA supplementation. Moreover, NM also failed to further reduce MMP7 and -defensin expression, AKK abundance, and butyrate levels in intestinal VDR-silenced mice. Finally, VD3 remodeled the gut microbiome particularly enriching AKK, increased butyrate contents and promoted the expression of -defensins, MMP7, and VDR, thereby attenuating NM-induced skin damage. The protective effect of VD3 against NM-caused dermal toxicity was abolished by either ABX or intestinal-specific knockdown of MMP7 or VDR in mice; however, this impairment was reversed by butyrate or AKK. In conclusion, VD3 attenuated NM-caused dermal toxicity by promoting BA production via remodeling the gut microbiota, and this effect was partially mediated by the intestinal VDR--defensin signaling pathway. These highlight that targeting the gut flora or supplementing with BA could be potential therapies for NM-induced dermal toxicity.

molecular biology↗

bioRxiv2026

High resolution interaction surface mapping by PRISMA reveals novel ARID1A interactions

The SWI/SNF chromatin remodelling complex controls proliferation and cell fate determination by regulating chromatin accessibility at promoters and enhancers, thereby modulating programs of gene expression, and has roles in DNA damage response, replication, splicing, and translation, and cell plasticity. The cBAF-exclusive subunit ARID1A acts as scaffold for the assembly of cBAF SWI/SNF complexes through its C-terminal globular domain and is the most frequently mutated SWI/SNF subunit in cancer. More than half of the ARID1A protein sequence contains regions of intrinsic disorder which are important for protein interactions, often mediated by short linear motifs. However, these interactions are notoriously difficult to study. Whilst hundreds of ARID1A interactions have been reported in the literature, their molecular basis remains obscure, and only a few have been explored functionally or mapped at an interface level. Here, we use a PRotein Interaction Screen on a peptide MAtrix (PRISMA) combined with quantitative mass spectrometry to identify novel ARID1A interactions and map amino acid residues and motifs that mediate interactions at high sequence resolution. The ARID1A PRISMA assay recapitulates binding of BAF subunits to ARID1A and detects the previously described binding of YAP1 transcriptional coactivator to a PPXY motif. Our PRISMA data reveals binding sites for transcriptional repressor SIN3A and identifies TOX4, CDK2 and CCNA2 as novel interactors. Mutation of a cell cycle-dependent CDK2 phosphorylation site in ARID1A leads to altered gene expression of microtubule factors and defects in cell proliferation. Our work underscores the utility of PRISMA to uncover weak or low abundance interactions that are not detectable by traditional affinity purification strategies. Together, our results characterise novel interactors and a new mode of regulation of ARID1A, and provide a useful resource to further explore mechanistic aspects of ARID1A function.

biochemistry↗

bioRxiv2026

A dimer peptide ligand of vascular endothelial growth factor slows the progression of human gastric tumors in mouse xenografts

Gastric cancer is among the most common cancers and represents a major public health problem worldwide. New therapeutic strategies and drugs are needed. Anti-angiogenic agents targeting the Vascular Endothelial Growth Factor (VEGF) are used in combination therapy in the clinic, although their efficacy remains modest. We believe that these large anti-VEGF antibodies could be advantageously replaced by smaller peptides with better tissue penetration. In this study, we evaluate the efficacy of a previously described dimer peptide ligand of VEGF, D6, in inhibiting the proliferation of gastric cancer cells and the growth of the corresponding murine xenograft. The activity of the D6 peptide in these assays was comparable to that of bevacizumab, the positive control antibody, although the peptide required repeated injections at higher molar concentrations. These promising results justify the continued optimization of the peptide dimer, currently under investigation in our laboratory.

pharmacology and toxicology↗

bioRxiv2026

The schizophrenia associated protein DISC1 is a multivalent tetrameric hub of conserved ancient fold

DISC1 is a pleiotropic protein with essential roles in neuronal proliferation and migration, intracellular signalling and cargo transport. It associates with a diverse array of partner molecules in these contexts. Mutations at the DISC1 locus are strongly associated with a spectrum of mental illnesses such as schizophrenia and depression. Despite its clinical relevance, the molecular architecture and function of DISC1 have remained largely elusive. We present a cryo-EM structure of the entire conserved core region of DISC1. The structure reveals an intricate homotetrameric assembly that harbours conserved bacteria-derived UVR domains. Four of these domains, one from each monomer, mediate extensive contacts forming two asymmetric dimer units. The dimers in turn interface with each other at two distinct coiled coil domains to achieve a two-fold symmetric tetramer. Mutational analysis shows that this tetrameric architecture enables DISC1 to simultaneously bind multiple copies of NDE1 client protein. Importantly, tetramerization and partner binding are structurally independent functions of DISC1. Altogether, our study provides a compelling molecular model of an ancient bacteria protein fold participating in the assembly of a multivalent mammalian scaffold hub that can coordinate multiple partner molecules.

neuroscience↗

bioRxiv2025

An EEG-based Multi-Scale Hybrid Attention and Squeeze Network for objective taste assessment

Taste perception is central to flavor experiences. Electroencephalography (EEG) signals carry rich information about taste perception. Because these neural data are independent of verbal reports and bypassing conscious filtering, EEG holds promise as a neural-sensing platform for objective taste representation. However, taste-evoked EEG signals exhibit complex spatiotemporal and spectral dynamics that require advanced computational approaches to decode effectively. This study developed an EEG-based Multi-Scale Hybrid Attention and Squeeze Network (MHASNet) for taste evaluation. EEG signals evoked by distinct taste stimuli were recorded, a dedicated taste-EEG dataset was compiled, and a novel deep learning architecture, MHASNet, was designed to classify these signals. MHASNet synergistically integrates multi-scale convolutions to capture temporal dynamics across different time scales, dual-attention mechanisms to localize discriminative brain regions and electrode positions, and a squeeze-and-excitation module to optimize frequency-band contributions-collectively enabling precise extraction of taste-specific neural signatures. Results showed that the proposed model achieved superior performance across five taste categories (sweet, sour, salty, bitter, and tasteless), with 94.33% accuracy, 91.37% F1-score, 91.89% precision, and 92.07% recall. These results surpass benchmark models while maintaining millisecond-level inference latency suitable for real-time applications. By complementing subjective evaluations and instrumental analyses, the model offers an objective, neurophysiology-based solution for taste evaluation.

neuroscience↗

bioRxiv2025

Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy

BackgroundThe vitamin D receptor (VDR) regulates insulin sensitivity. Metabolic bariatric surgery (MBS) remains the most effective treatment for obesity and T2D. However, whether its metabolic effects are VDR-dependent is unknown. Here, we assessed VDR role in the metabolic response to sleeve gastrectomy (SG). MethodsWhole body VDR knockout (KO) and wild type (WT) C57BL/6J mice with diet-induced obesity (DIO) were assigned to either SG or sham procedure. Postoperatively, animals underwent glucose and insulin tolerance tests. On sacrifice, serum, white adipose tissue (WAT), liver and colonic contents were collected for further biochemical, histological and bile acid analysis. Separately, human VDR gene expression was assessed in subcutaneous adipose tissue (SAT) biopsies collected from patients with/without MBS history. ResultsKO SG mice exhibited delayed glucose utilization after an oral challenge and progressive loss of insulin sensitivity, despite the same magnitude of surgery-induced weight change between the two genotypes. WAT in KO SG mice had lower mass, smaller adipocytes and increased inflammation. SG had a differential effect on colonic levels of the glucoregulatory cholic acid 7-sulfate (CA7S): increasing CA7S concentration in the WT mice but decreasing it in the KO mice. Finally, patients with MBS history had higher VDR expression in SAT as compared to those without MBS history. ConclusionVDR is necessary for metabolic health after SG in DIO mice due to its role in WAT function, insulin sensitivity and inflammatory response after surgery. Increased expression of VDR in patients post-MBS suggests that it may also contribute to metabolic responses in humans. HighlightsO_LIVDR KO results in delayed glucose utilization following SG in DIO mice C_LIO_LIVDR KO results in progressive loss of improved insulin sensitivity after SG C_LIO_LIVDR KO results in white adipose tissue inflammation and remodeling after SG C_LIO_LIVDR expression increases in human subcutaneous adipose tissue after bariatric surgery C_LI

physiology↗

bioRxiv2025

A TP53 Intron-Derived Peptide Promotes Tumor Survival

During transcription, alternative cleavage and polyadenylation (APA) of transcripts produces mRNAs that differ in their 3 ends. We previously found that leukemia cells cleave and polyadenylate transcripts within introns (intronic APA, IPA) to generate truncated RNA isoforms, which perturb the expression and function of corresponding genes. In addition to protein-coding RNA, we found that leukemia cells express numerous putative long non-coding RNAs generated by IPA, with most uncharacterized. Here, we identify an IPA isoform encoded within intron 1 of the TP53 tumor suppressor gene that is translated into a non-canonical protein termed IPADP1 (IPA-derived protein 1). IPADP1 expression was detected in patient leukemia cells and human blood cancer cell lines. We uncovered an oncogenic role for IPADP1 in enhancing cancer cell survival during drug treatments, as well as promoting tumor formation in vivo. Using proteomic and functional studies, our data suggest that IPADP1 increases cell viability by regulating apoptotic signaling, cell cycle, and DNA damage responses. Furthermore, we observed that the expression of p53-IPA is significantly associated with SF3B1 mutations in leukemia patients, suggesting mechanisms for the genesis of this isoform. Our study demonstrates that an IPA isoform could have a function different from its host gene.

cancer biology↗

bioRxiv2025

Reconstructing the Ischemic Cerebrum by Transplanted Human Neurons

Neural transplantation holds the potential to repair damaged neural circuits in neurological diseases. However, it remains unknown how the grafted neurons project axons to and make functional connections with the appropriate targets to repair the damaged circuit at the adult stage. Here we report that human cortical progenitors, transplanted into the ischemic mouse motor cortex, matured and integrated into cortical and subcortical neural circuits including the corticospinal tract. Neuronal tracing combined with single-nuclei RNA sequencing revealed the close relationship between the transcription profiles of a cortical neuronal subtype, especially those of axon guidance and synapse assembly, with the specific target projection and synapse organization. Machine learning-based regression further identified the transcriptional codes for the targeted projection and circuit integration to reconstruct the damaged circuits. Our finding opens a promising strategy for treating neurological diseases through promoting regeneration and neural transplantation. HighlightsHuman ESC-derived cortical neurons reconstitute the ischemic motor cortex Functionally repaired corticospinal tract restores animal behaviors Transplanted cortical neurons exhibit subtype-specific projection and integration Unique transcriptional coding for axonal navigation in the mature CNS

neuroscience↗

bioRxiv2025

The Inaugural Flatiron Institute Cryo-EM Conformational Heterogeneity Challenge

Despite the rise of single particle cryo-electron microscopy (cryo-EM) as a premier method for resolving macromolecular structures at atomic resolution, methods to address molecular heterogeneity in vitrified samples have yet to reach maturity. With an increasing number of new methods to analyze the multitude of heterogeneous states captured in single particle images, a systematic approach to validation in this field is needed. With this motivation, we issued a challenge to the community to analyze two cryo-EM particle image sets of thyroglobulin that exhibit continuous conformational heterogeneity. The first dataset was experimental and the second was generated with a simulator, allowing control over the distribution of molecular structures and enabled direct comparison between participants submissions and the ground truth molecular structures and distributions. Participants were asked to submit 80 volumes representing the heterogeneous ensemble and estimate their respective populations in the image sets provided. Participation of the research community in the challenge was strong, with submissions from nearly all developers of heterogeneity methods, resulting in 41 submissions across both datasets. Submissions qualitatively exceeded expectations, with the molecular motions identified by methods resembling both each other and the ground truth motion. However, quantitatively assessing these similarities was a challenge in and of itself. In the process of assessing the submissions, we developed several validation metrics, most of which require reference to the underlying ground truth volumes. However, we have also explored the use of metrics that do not necessarily reference ground truth. This is particularly apt for experimental datasets where ground truth is inaccessible. These approaches allowed us to assess the similarity and accuracy in volume quality, molecular motions, and conformational distribution of di!erent submissions. These metrics and the e!orts of all participants help chart a path forward for the improvements of heterogeneity methods for cryo-EM and for future challenges to validate these new methods as they continue to be developed by the community.

biophysics↗

bioRxiv2025

Real-time visualization of ligand-specific conformational dynamics of GPCR C-terminal domain in living cells

The cytoplasmic tails (C-tails) of membrane receptors are fundamental hubs for signal transductions. Yet directly investigating their dynamics in living cells is challenging. We developed a single-molecule technique to sense C-tail's conformational transitions. It was applied to investigate the ligand-induced activation of {beta}2AR, a prototypical G protein-coupled receptor (GPCR). Our data elucidate how the receptor transduces ligand binding to cell-level outcomes, with the ligand efficacy being interpreted in terms of the association and disassociation rates of the G protein. Moreover, upon G protein binding, not only the C-tail is displaced from the intracellular surface of the receptor but also the eighth helix H8 is dissociated from the plasma membrane. This work establishes a robust framework to directly decipher the activation of membrane receptors without interferences from overexpressed downstream transducers.

biophysics↗

bioRxiv2025

Bromodomain protein IBD1 bridges histone acetylation and H2A.Z deposition to fine-tune transcription and prevent hyperactivation in Tetrahymena thermophila

Eukaryotic gene expression is dynamically regulated through the interplay between histone modifications and chromatin remodeling, yet how these processes are coordinated remains incompletely understood. Here, we identify IBD1 as a critical adaptor that bridges histone acetylation and SWR-mediated H2A.Z deposition. We demonstrate that the bromodomain of IBD1 recognizes histone acetylation, specifically H3K9/14 di-acetylation to recruit the SWR complex subunit ARP6, ensuring precise H2A.Z incorporation into chromatin. Genetic disruption of IBD1, either by deletion or bromodomain mutation, attenuates H2A.Z occupancy at target loci, confirming its essential role in H2A.Z deposition. Strikingly, perturbation of the histone acetylation-IBD1-H2A.Z axis triggers transcriptional hyperactivation, revealing a dual function of H2A.Z in sustaining basal transcription while preventing aberrant gene induction. This defines a novel regulatory paradigm in which IBD1 couples acetyl-mark decoding to SWR-dependent H2A.Z deposition, establishing transcriptional homeostasis. Our findings resolve a central ambiguity by demonstrating that H2A.Z acts as a repressive buffer in highly acetylated regions, counterbalancing the inherent activation potential of acetylation. This study provides a framework for investigating H2A.Z functions and reveals new perspectives on how chromatin modifications and histone variants interplay in transcriptional regulation.

genetics↗

bioRxiv2025

STRESS: Spatial Transcriptome Resolution Enhancing Method based on the State Space Model

The widespread application of spatial resolved transcriptomics (SRT) has provided a wealth of data for characterizing gene expression patterns within the spatial microenvironments of various tissues. However, the inherent resolution limitations of SRT in most published data restrict deeper biological insights. To overcome this resolution limitation, we propose STRESS, the first deep learning method designed specifically for resolution enhancement tasks using only SRT data. By constructing a 3D structure that integrates spatial location information and gene expression levels, STRESS identifies interaction relationships between different locations and genes, predicts the gene expression profiles in the gaps surrounding each spot, and achieves resolution enhancement based on these predictions. STRESS has been trained and tested on datasets from multiple platforms and tissue types, and its utility in downstream analyses has been validated using independent datasets. We demonstrate that this resolution enhancement facilitates the identification and delineation of spatial domains. STRESS holds significant potential for advancing data mining in spatial transcriptomics.

bioinformatics↗