Biology subjects

Ren, B.

Publications and source records attributed to Ren, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Integrative Single-Cell Epigenomic Atlas Annotates the Regulatory Genome of the Adult Mouse Brain

Histone modifications underpin the cell-type-specific gene regulatory programs that drive the remarkable cellular diversity of the mammalian brain. Here, we jointly profiled four histone modifications and the transcriptome in 2.5 million nuclei from the adult mouse brain. By integrating these data with chromatin accessibility, DNA methylation, and three-dimensional genome organization, we constructed a unified epigenomic atlas spanning over 100 brain cell subclasses, and assigned active, primed, and repressive chromatin states across 81% of the genome. Active chromatin states marked by combinatorial histone modifications better nominate candidate enhancers with functional support than chromatin accessibility alone, while H3K27me3- and H3K9me3-marked chromatin states delineate distinct modes of cell-type-specific gene repression. Finally, this multimodal resource enables deep learning models that predict cell-type-specific epigenomic features and gene expression from DNA sequence, providing a comprehensive framework for annotating the brain regulatory genome and interpreting non-coding disease risk variants. HIGHLIGHTS- A single-cell epigenome atlas of transcription and four histone modifications across 2.5M mouse brain cells - Multimodal integration maps chromatin states across [~]81% of the adult mouse brain genome - Cell-type-resolved chromatin landscapes reveal regulatory programs mediated by enhancers, Polycomb and H3K9me3 - Deep learning models predict cell-type-specific epigenomic features and gene expression from DNA sequence

genomics↗

bioRxiv2026

An Integrated Single-Cell and Epigenomic Resource for Comparative Analysis of the Basal Ganglia

The basal ganglia regulate motor, cognitive, and affective behaviors, and their dysfunction underlies diverse neurological and psychiatric disorders. Comprehensive, accessible multi-omics resources are needed to understand the regulatory mechanisms governing basal ganglia cell types. Here we present an open, interactive web-based platform for exploring single-cell multi-omics datasets from basal ganglia, generated using 10X Multiome, snm3C-seq, and Paired-Tag technologies from the BICAN (NIH BRAIN Initiative Cell Atlas Network) consortium. The platform is available at https://basalganglia.epigenomes.net/ and enables integrated visualization of gene expression, chromatin accessibility, DNA methylation, histone modifications, and chromatin conformation across cell types and human, macaque, marmoset, and mouse species, with direct genome browser support and comparative epigenomic functionality. Representative analyses demonstrate cell-type-specific regulatory landscapes, conserved and species-specific regulatory elements, and links between epigenomic regulation and transcription. This resource provides a scalable, community-oriented foundation for advancing basal ganglia biology and interpreting regulatory mechanisms relevant to brain function and disease. HighlightsO_LIIntegrated single-cell epigenomic resource for basal ganglia C_LIO_LIInteractive genome browser enables multi-omics and cross-species exploration C_LIO_LIReveals cell-type-specific and species-specific regulatory landscapes C_LIO_LISupports community access to complex brain epigenomic datasets C_LI

genomics↗

bioRxiv2026

SUMO2 Deletion Changes Chromatin Accessibility and Enhances Cytotoxic T Cell Activation and Tumor Infiltration

Cytotoxic T cells (CTL) are crucial for adaptive immunity that leads to prolonged survival and potential cures for cancer. Recent clinical data has shown that pharmacological inhibition of SUMOylation (SUMOi) profoundly modifies tumor microenvironment (TME) and activates CTL, although the mechanism is not well described. In this study, we found that T cell specific knock out (KO) of the most dominant SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation that is independent of the known mechanism - inducing type I IFN (IFN-I) expression by myeloid cells. Sumo2/SUMO2 KO in CD8+ T cells increased chromatin accessibility for transcription factors BATF, JunB, ATF3, FRA1, FRA2, and AP1 that are known to promote T cell activation and proliferation. Using antigen-specific T cell models, OT1 and Chimeric Antigen Receptor (CAR)-T cells, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration as revealed by flow cytometry, immuno-fluorescence (IF) staining, and single nuclei RNA-sequencing (snRNA-seq) and conferred greater tumor growth inhibition than wildtype (WT) control T cells. snRNA-seq also revealed Sumo2 KO CD8+ T cells increased the expression of Tumor Necrosis Factor-Related Apoptosis-inducing Ligand (TRAIL), induced apoptosis genes in tumor cells and activated IFN-I and IFN-{gamma} responsive genes in all cell types in the TME. These findings elucidate a novel mechanism regarding how SUMOylation can directly control CTL activation and tumor infiltration that activate anti-tumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies of solid tumors by enhancing their activity, tumor infiltration and their ability to after the TME.

immunology↗

bioRxiv2026

Chromosome-level genome assembly and annotation of the degu (Octodon degus)

High-quality reference genomes are essential for comparative and functional genomics yet remain unavailable for many emerging model organisms. Here, we report OctDeg2.0, a chromosome-level genome assembly and annotation of the degu (Octodon degus), generated using PacBio HiFi long-read sequencing and Hi-C scaffolding from a single male individual. Octodon degus is of growing interest as a natural animal model for aging and Alzheimers disease research. The 3.4 billion base-pair assembly comprises 28 autosomes and both sex chromosomes, with markedly improved contiguity and completeness over the prior short-read assembly while maintaining high base accuracy. The new assembly provides substantially enhanced gene annotation, clearer resolution of chromatin architecture and cis-regulatory element landscapes, with much improved characterization of repetitive and structurally complex regions, including centromeres and segmental duplications. We present a streamlined and reproducible pipeline for high-resolution de novo genome assembly and gene annotation applicable to other emerging model organisms. This work establishes a robust genomic resource for studying molecular and cellular mechanisms in health and disease in Octodon degus.

genomics↗

bioRxiv2026

A Manifold-Based Measure of Transcriptional Entropy for Quantifying Aging in Single Cells

Aging reshapes tissues through changes in cellular composition, coordinated transcriptional reprogramming, and loss of transcriptional coordination. Whereas the first two have been characterized across aging tissues, the third remains difficult to quantify. We introduce an unsupervised, first-principles framework for measuring transcriptional dyscoordination in single cells as deviation from a learned, predictable structure accounting for technical noise. Orthogonal validation links transcriptional dyscoordination to classical intrinsic noise and distinguishes it from coordinated change. In controlled perturbations, dyscoordination rises after genotoxic injury and senescence induction, then falls following senolytic depletion. Across mouse, rat, and human tissues, dyscoordination increases with chronological age, especially in regenerative compartments. In human T cells, dyscoordination increases with clonal expansion and effector function yet declines within persisting clones after checkpoint blockade. Cross-modal analyses further link dyscoordination to chromatin-based mitotic age and genome instability. These results identify loss of transcriptional coordination as a distinct and dynamic feature of cellular aging.

genomics↗

bioRxiv2026

TLR7 inhibition limits cardiac ischemic injury by disrupting ITGAM-dependent immune-endothelial interaction

Percutaneous coronary intervention (PCI) limits ischemic myocardial infarction but also triggers ischemia-reperfusion (I/R) injury in part driven by innate immune activation. Here, we identify Toll-like receptor 7 (TLR7), an endosomal sensor of single-stranded RNA, as a mediator of post-ischemic inflammation and myocardial damage. Pharmacological inhibition of TLR7 with enpatoran reduced myocardial inflammation and infarct size and improved cardiac function in a mouse model of I/R injury when administered before, during, or shortly after ischemia. Single-nucleus RNA sequencing revealed coordinated post-I/R expansion of myeloid cells and distinct inflammatory endothelial subsets enriched for leukocyte-interaction programs, with marked upregulation of Itgam in cardiac leukocytes and endothelial cells and in circulating monocytes. Circulating ITGAM+ monocytes were similarly increased in patients with ST-segment elevation myocardial infarction 24 hours after coronary stenting. Mechanistically, TLR7 activation induced Itgam expression in endothelial cells and leukocytes and promoted their adhesion via ITGAM-ICAM1 interaction under physiological shear stress, whereas ITGAM neutralization disrupted this interaction, reduced immune cell infiltration, and limited ischemic injury. These findings define a TLR7-ITGAM signaling axis as a key driver of endothelial-leukocyte crosstalk in myocardial I/R injury and support TLR7 inhibition as a promising therapeutic strategy to mitigate acute myocardial infarction.

immunology↗

bioRxiv2025

UC Irvine Brain Initiative Cell Atlas Network (BICAN) Brain Procurement Program for the Center for Multiomic Human Brain Cell Atlas Project

High-quality neurotypical postmortem human brain tissue is essential but difficult to obtain for constructing comprehensive human brain cell atlases. Here we describe the establishment of UC Irvines Brain Procurement Program, a coordinated initiative to collect and process neurotypical donor brains for multiomic mapping studies within the NIH BRAIN Initiative Cell Atlas Network (BICAN) consortium. Through partnerships with the Orange County Coroners Office, the UC Irvine Willed Body Program, UCI Medical Center, and the Childrens Hospital of Orange County, we have developed standardized workflows encompassing donor identification, postmortem brain recovery and processing, region-of-interest dissection, neurotypical donor selection, and data management. Our experience demonstrates the feasibility of a community-based, multi-institutional procurement framework while highlighting challenges in recruiting neurotypical donors and ensuring demographic representation reflective of Southern California. We further identify opportunities to strengthen outreach and donation pathways. This program provides a scalable model for advancing population-reflective, high-quality human brain cell atlas efforts. HighlightsO_LIEstablish a multi-site pipeline for procuring high-quality neurotypical human brains. C_LIO_LIDemonstrate feasibility of donor collection across childhood to adulthood. C_LIO_LIIdentify barriers and propose strategies to improve broad donor recruitment. C_LI

neuroscience↗

bioRxiv2025

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

cell biology↗

bioRxiv2025

Innovative Prevention Approach for Pan Allergens-Induced Allergy: Effective Regulation of Heat Shock Protein 70 and Profilin 3 by siRNA-Loaded Nanomaterial

Currently, the widely accepted approach to addressing pollen allergy primarily through altering the immune system of patients. However, the great potential of genetic engineering for downregulating allergenic proteins and reducing allergenicity is often overlooked in previous studies. Here, we report an effective solution to reducing plant allergenicity by utilizing RNA interference (RNAi) technology to calibrate levels of pan-allergenic proteins Heat Shock Protein 70 (HSP 70) and Profilin 3 (PFN 3) in transgenic Arabidopsis, Tobacco, and Osmanthus. This has been shown in research to effectively mitigate and prevent allergenic reactions in humans. 21-bp long siRNA sequences encased by Polyethyleneimine modified carbon dots (PEI-CDs) are synthesized to constitute a nanoparticle-mediated delivery system to efficiently deliver small-interfering RNA (siRNA) vectors into plants. Afterwards, RNA was extracted from Osmanthus fragrans and Gardenia jasminoides and underwent reverse transcription quantitative-polymerase chain reaction (RT-qPCR). The result indicated the expected suppression of mRNA corresponding to the targeted proteins, proving the functional aspect of RNAi in allergen suppression trunk injection and suggesting its applicability in real-life scenarios.

synthetic biology↗

bioRxiv2025

Multiscale Spatial Transcriptomic Atlas of Human Basal Ganglia Cell-Type and Cellular Community Organization

We generated a multi-region, subcellular-resolution spatial transcriptomic atlas of the human basal ganglia by integrating MERFISH+ and Stereo-seq across four neurotypical donors. These datasets profiled [~]7 million cells spanning the caudate, putamen, nucleus accumbens, and globus pallidus, resolving 60 transcriptionally distinct cell types. We show region-selective, molecular and spatial diversification of medium-spiny-neuron cell types and multiple non-neuronal populations with distinct molecular identities and spatial localizations. Subcellular RNA localization captures somatic size and projection-inferred signatures that reflect direct and indirect pathway topology. Cellular community analyses reveal the enrichment of sub-clusters of astrocytes and oligodendrocytes at striosome-matrix borders, while primate-expanded interneurons are confined to matrix territories. Cross-species mapping uncovers orthologous striosome-matrix organization and conserved dorsolateral-ventromedial gene expression gradients. This atlas provides a foundational molecular and spatial framework for studying human basal ganglia architecture, offering a multi-centimeter scale resource that links cell types, spatial architecture, and subcellular transcript topography across multiple nuclei. HighlightsO_LIOur multi-centimeter scale spatial taxonomy identifies the precise locations of 60 neuronal and glial cell types of human basal ganglia. C_LIO_LIMERFISH+ and Stereo-seq platforms map consistent spatial modules that align with classical neuroanatomical nuclei. C_LIO_LID1D2 hybrid MSNs and primate-expanded interneurons show regional and domain specific organization C_LIO_LISubcellular RNA localization reports soma morphology and projection-inferred signatures. C_LI

neuroscience↗

bioRxiv2025

Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease

Alzheimers disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas--integrating DNA methylation and 3D genome architecture--from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.

genomics↗

bioRxiv2025

Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality

Distinct regional functionality of the human cortex is orchestrated by diverse cellular and molecular processes, yet the underlying regulatory mechanisms remain poorly understood. We performed multiomic single-cell and spatial characterization of nine regions of the human cortex to define the gene regulatory networks and transcription factors that govern cell-type and region specificity. With the combined data of over three million cells, two striking patterns of cortical neuron specialization were uncovered: a rostral-caudal gradient of calcium regulatory machinery, and subunit switching of multiple signaling receptor families across the transmodal-sensory axis. Gene regulatory network analysis revealed putative transcriptional regulators of cortical neuron specialization with cell-type- and region-specific gene regulation patterns. While regionalization was observed in gene expression, chromatin accessibility, and spatial distributions, these modalities exhibited distinct cortical patterns. Our findings illuminate critical neuronal pathways that vary throughout the cortex and the gene regulatory networks that establish cortical regionalization in the human brain.

neuroscience↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗

bioRxiv2025

An artificially selected cytokinin-pathway transcription factor balances soybean yield and pathogen resistance

Soybean contributes to sustainable food and feed production, but some modern varieties favor yield at the cost of disease resistance. Using a bottom-up approach, we demonstrate that the RR2b transcription factor activates cytokinin signaling for plant growth and reproductive fitness but represses disease-resistance and root-nodulation pathways. RR2b was artificially selected during domestication and improvement, and its expression levels correlate with ATT repeat polymorphisms in its promoter. Most wild soybeans and landraces have either more or less ATT repeats: more lead to weak RR2b expression with lower yield and enhanced resistance to soybean bacterial blight, and fewer cause strong RR2b expression, higher yield but reduced disease resistance. Elite cultivars instead balance yield and defense via moderate RR2b expression and several ATT repeats. This confers contrasting RR2b functionality across haplotypes in response to contrasting selection pressures and offers insights into decoupling trade-offs between yield and disease resistance to enhance crop productivity.

genetics↗

bioRxiv2025

Single-Cell Epigenomics Uncovers Heterochromatin Instability and Transcription Factor Dysfunction during Mouse Brain Aging

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-responsive programs driven by AP-1, indicating a progressive loss of cell identity with aging. We also identify region- and cell-type-specific heterochromatin decay, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long non-coding RNAs, particularly in glutamatergic neurons. Together, these results reveal age-related disruption of heterochromatin maintenance and transcriptional programs, identify vulnerable brain regions and cell types, and pinpoint key molecular pathways altered in brain aging. HighlightsO_LISingle-cell multimodal profiling across eight brain regions reveals coordinated chromatin and transcriptional shifts during aging C_LIO_LIAge-related depletion of progenitor cells coincides with dysregulation of key developmental transcription factors C_LIO_LICell identity maintenance is compromised with the decline of master transcription factors C_LIO_LIHeterochromatin destabilization accompanied by activation of AP-1, transposable elements, pseudogene families, and long non-coding RNAs C_LI

genomics↗

bioRxiv2025

Cell-type-specific transposable element demethylation and TAD remodeling in the aging mouse brain

Aging is a major risk factor for neurodegenerative diseases, yet underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that age-related methylation changes were more pronounced in non-neuronal cells. Transposable element methylation alone distinguished age groups, showing cell-type-specific genome-wide demethylation. Chromatin conformation analysis demonstrated age-related increases in TAD boundary strength with enhanced accessibility at CTCF binding sites. Spatial transcriptomics across 895,296 cells revealed regional heterogeneity during aging within identical cell types. Finally, we developed novel deep-learning models that accurately predict age-related gene expression changes using multi-modal epigenetic features, providing mechanistic insights into gene regulation. This dataset advances our understanding of brain aging and offers potential translational applications. HighlightsO_LISingle-cell multi-omic profiling maps the epigenetic and spatial transcriptomic landscape of brain aging across multiple regions. C_LIO_LICell-type-specific genome-wide demethylation of retrotransposable elements correlates with increased chromatin accessibility and expression. C_LIO_LIElevated TAD boundary strength emerges as a unique marker of brain aging associated with CTCF gaining accessibility. C_LIO_LIA novel deep-learning model reveals the significance of epigenetic features on age-related transcriptomic changes across genes. C_LI

genomics↗

bioRxiv2025

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Intriguingly, extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, indicating that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers an extensive reference for exploring gene regulation in human health and disease.

genomics↗

bioRxiv2025

Activity of Human-Specific Interlaminar Astrocytes in a Chimeric Mouse Model of Fragile X Syndrome

Astrocytes, a subtype of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome. We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and are associated with dendritic spines with increased turnover rate.

neuroscience↗