Biology subjects

Ruan, Y.

Publications and source records attributed to Ruan, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Transient tubular membrane injury is converted into persistent fibrosis through a macrophage-fibroblast relay

A central unresolved problem in acute kidney injury (AKI) is how a transient epithelial insult is converted into persistent fibrotic repair that drives progression toward chronic kidney disease. Although tubular, immune and stromal responses are individually well recognized, the mechanistically continuous relay linking these three compartments has remained unresolved. Here we define a directional information-conversion pathway spanning injured tubular epithelial cells, macrophages and fibroblasts. Time-resolved single-cell profiling identified a TREM2/SPP1 macrophage state that emerged as post-ischemic repair became fibrotic. Tubular injury remodeled phosphatidylserine (PS) species, increased oxidized PS and PS externalization, and generated a membrane-lipid context for TREM2 sensing, supported by PS masking, defined liposomes and orthogonal binding assays. Structure-function analysis separated R47-dependent phospholipid recognition from K183-dependent DAP12 coupling, linking membrane damage to SYK activation and NF-kB/AP-1-driven Spp1 transcription. Macrophage-derived SPP1 then activated ITGAV/ITGB1-associated FAK-SMAD2/3 signaling, fibroblast contraction and matrix production. Crucially, repair-phase SPP1 neutralization and post-injury Cx3cr1-lineage Trem2 deletion attenuated fibrosis, with delayed Trem2 deletion protective in both ischemic and obstructive injury. Human single-cell, spatial, urinary and tissue analyses showed cross-species and cross-scale convergence. These findings resolve how transient tubular membrane damage is successively transformed across three cellular compartments into persistent, yet interruptible, fibrotic repair.

pathology↗

bioRxiv2026

Xenon improves autism-like behaviors in mice through potentiation of PVT-CeA glutamatergic neurotransmission

Autism spectrum disorder (ASD) is a common neurodevelopmental disease with no currently effective treatments. In this study, Xenon (Xe), a noble gas used clinically as an anesthetic and a neuroprotectant, has been investigated for its potential therapeutic effects in ASD. Two genetic ASD mouse models (Mef2c mutant and Shank3-/- mice) were exposed to a low concentration of xenon (25%) mixed with oxygen (30%) and balanced with nitrogen for a single exposure of 30 min or for 10 min per day for 10 days. These Xe exposure paradigms rescued ASD-like behaviors in both male and female mice. The behavioral improvements persisted for up to 10 days following termination of the 10-day exposure paradigm. Mechanistically, Xe reduced glutamic acid decarboxylase expression in the inhibitory neurons (verified with RNAseq) of the paraventricular thalamic nucleus (PVT) and decreased GABA release during social interaction. Targeted infusion of the GABAA receptor agonist muscimol into the PVT abolished the Xe-mediated behavioral improvements. Reduced GABAergic transmission following Xe exposure increased PVT glutamatergic neuronal activity. Chemogenetic inhibition of these neurons eliminated the therapeutic effects of Xe, whereas chemogenetic activation mimicked the Xe-induced behavioral improvements. Furthermore, opto-inhibition of PVT glutamatergic projections to the central amygdala (CeA) blocked Xe-mediated behavioral improvement. Opto-activation of the PVT-CeA glutamatergic circuit reversed ASD-like behaviors. These findings demonstrate that Xe ameliorates ASD-like phenotypes in mouse models by modulating the PVT Glu-CeA circuit, supporting Xe as a novel potential therapy for ASD.

animal behavior and cognition↗

bioRxiv2026

Pathology in resected areas of FDG PET hypometabolism in pediatric epilepsy patients with focal cortical dysplasia

Introduction[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) frequently reveals hypometabolism extending beyond the epileptogenic zone in focal cortical dysplasia (FCD). However, it is unclear whether these peripheral hypometabolic areas harbour pathological cells potentially contributing to seizure generation. This study characterized histopathology in the lesion epicentre vs borders of the FDG-PET hypometabolism-informed resections in pediatric patients undergoing epilepsy surgery. MethodsFourteen children with intractable, extra-temporal focal epilepsy (mean age 9.0{+/-}5.0 years; 9 female) were retrospectively reviewed. FDG-PET contributed significantly to surgical planning in all cases, with the resection encompassing the visually-apparent MRI signal abnormalities as well as areas of surrounding hypometabolism when safely feasible. Multiple pathological specimens were obtained from the epicentre and surrounding hypometabolic areas. Overall, 136 specimens were analyzed: 64 epicentre (mean 4.6{+/-}3.2/patient) and 72 border (mean 5.1{+/-}3.5/patient). ResultsPathology was identified in 75% of epicentre specimens (59% with frank FCD (fFCD) IIa/b, 16% with dysmorphic neurons only (DNO)). Border specimens showed pathology in 62% (31% fFCD IIa/b, 31% DNO). We fitted a Bayesian logistic mixed model with pathology as outcome variable, location as predictor, and subject as a random effect. Compared to negative pathology, the log-odds of fFCD in the epicentre was 1.00 (confidence interval (CI) 0.32, 1.77) and -1.25 in the border (CI -2.17, -0.40). The log-odds of DNO vs negative pathology was non-significant in both locations. All patients achieved Engel Ia status at one-year follow-up with no long-term neurological deficits. ConclusionThese findings suggest a gradient of histopathology, with fFCD concentrated in the epicentre and DNO present in both the epicentre and hypometabolic borders. Thus, FDG-PET may be used to better detect the histopathological borders of FCD type II, and the high seizure-freedom rate presented here supports the inclusion of these surrounding hypometabolic regions in the surgical resection (when safe to do so), potentially improving the likelihood of removing epileptogenic cells. Key PointsO_LIPathological cells are present not only in the MRI signal abnormality in FCD but also in the periphery of the FDG-PET hypometabolism. C_LIO_LIWe observe a gradient of histopathology, with frank FCD concentrated in the epicentre and dysmorphic neurons spread throughout the area of hypometabolism. C_LIO_LIMaximal safe resection of the area of hypometabolism may increase likelihood of removing epileptogenic cells, thus improving surgical outcome. C_LI

neuroscience↗

bioRxiv2026

Cohesin extrudes chromatin loop unidirectionally through two modes of mechanisms in human cells

Cohesin is crucial for establishing 3D genome organization and functions. However, the in vivo mechanism of cohesin-mediated extrusion remains unsettled. Here, we investigated extrusion directionality using integrated genome mapping coupled with perturbation in human cells. By defining cohesin loading at NIPBL binding loci and anchoring at CTCF sites, we systematically characterized the aggregated and single-molecule trajectories of extrusion "stripes" and contact "dots" from and between individual cohesin loading and anchoring points. Our analyses delineated two dynamic modes of in vivo mechanism in which NIPBL/cohesin initiates extrusion at its loading sites in a one-sided manner; after encountering CTCF, CTCF/cohesin switches its extrusion direction backward and robustly extrude DNA unidirectionally until completing the convergent CTCF loop. Surprisingly, depleting CTCF resulted substantial increase of NIPBL/cohesin-mediated extrusion activity, which is further validated by in silico perturbation. These findings reveal novel mechanistic insights into how cohesin and CTCF orchestrate cohesin-mediated loop extrusion in vivo.

genomics↗

bioRxiv2026

Differentiable Gene Set Enrichment Analysis for Pathway-Level Supervision in Transcriptomic Learning

In transcriptomics-driven drug discovery, upstream predictors of chemical-induced transcriptional profiles (CTPs) are typically trained with gene-wise objectives, whereas downstream interpretation relies on pathway-level, rank-based statistics such as Gene Set Enrichment Analysis (GSEA). This objective mismatch destabilizes pathway conclusions under prediction errors: small ranking perturbations can flip enrichment direction or distort pathway ordering. To bridge this gap, we present differentiable GSEA (dGSEA), a training-compatible surrogate that maps predicted gene-level scores to pathway enrichment with well-behaved gradients. Technically, dGSEA replaces discrete ranking operations with temperature-controlled soft sorting, smooth prefix accumulation, and differentiable extremum aggregation. Critically, to preserve the statistical semantics of classical GSEA, we introduce sign-specific robust permutation normalization (dNES) with optional{kappa} -calibration. For computational efficiency, a scalable Nystrom-window approximation (nyswin) reduces the quadratic bottleneck to near-linear complexity, enabling genome-scale evaluation. Empirically, across synthetic benchmarks and LINCS L1000 signatures, dGSEA matches classical GSEA accuracy with improved numerical stability. When incorporated as an auxiliary objective for SMILES-to-transcriptome prediction, dGSEA improves pathway-level agreement (macro correlation 0.257 [->] 0.306; sign accuracy 0.620 [->] 0.641) without compromising gene-level performance, providing a practical mechanism for pathway-aware optimization in transcriptomic prediction pipelines.

bioinformatics↗

bioRxiv2026

Single-cell transcriptomic atlas of mouse oocyte development from growth to ovulation

Oocyte growth and maturation depend on tightly coordinated programs within oocytes and their surrounding granulosa cells, yet defining the transcriptional continuum of growing oocytes has been challenging due to their large size and the limitations of current droplet-based and spatial transcriptomic platforms. Here, we optimized a high-density array-based platform called Stereo-cell for high-throughput dual-modality profiling of large mouse oocytes, allowing for both the preservation of morphology and transcript capture. By integrating unsupervised transcriptomic clustering with cell morphological features, we delineated successive temporal windows from growing oocytes to metaphase II and uncovered stage-linked shifts from early programs toward later programs. We also profiled the ovarian somatic fraction, reconstructed granulosa-cell subtype relationships, and placed ovarian cell states in tissue context using single-cell-resolution spatial data.

developmental biology↗

bioRxiv2025

CRlSPR/Cas9 screening revealed BlRC6-AS1/BlRC6 mediates abiraterone resistance via NHEJ pathway-dependent A20 degradation in prostate cancer

Abiraterone acetate serves as the first-line therapeutic agent for prostate cancer (PCa) treatment. However, drug resistance frequently emerges. Employing a genome-wide CRISPR/Cas9 library screening strategy, we identified 523 long non-coding RNAs (lncRNAs) and 2183 protein-coding genes associated with abiraterone resistance. Notably, a pair of sense-antisense genes, BIRC6-AS1/BIRC6, was demonstrated to be a pivotal driver for abiraterone resistance. BIRC6-AS1 depletion led to a reduction in both the mRNA and protein levels of BIRC6. Moreover, depletion of either BIRC6-AS1 or BIRC6 enhanced the chemosensitivity of PCa cells to abiraterone both in vitro and in vivo settings. Further investigation revealed that BIRC6-AS1 stabilized the mRNA of BIRC6 through interaction with ILF2. Diminishing either BIRC6-AS1 or BIRC6 predominantly suppressed non-homologous end joining (NHEJ) repair activity, resulting in the disassembly of 53BP1 foci at DNA damage sites and an increased accumulation of DNA damage in PCa cells induced by abiraterone. Mechanistically, BIRC6 interacted with A20 and facilitated the K48-linked ubiquitination and subsequent degradation of A20 at the K337 residue. Additionally, A20 knockdown effectively reversed the abiraterone sensitivity induced by BIRC6-AS1 depletion. Collectively, we conducted a comprehensive screen to identify lncRNAs and protein-coding genes associated with abiraterone resistance and proposed that targeting BIRC6-AS1/BIRC6 axis represents a promising strategy to overcome abiraterone resistance in prostate cancer.

molecular biology↗

bioRxiv2025

Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure

Growing evidence indicates that immunological and metabolic outcomes are key mediators of long-term high-altitude exposure (LTHAE) adaption, but the underlying mechanisms remain poorly understood. This study employs plasma metabolomics and peripheral blood single-cell transcriptomic sequencing to analyze the metabolic and immune dynamic regulation in 46 young male lowlanders following a 90-day adaptation period at high altitude. Single-cell analysis shows a pattern of "innate immune activation and adaptive immune suppression" under LTHAE, characterized by facilitated maturation of neutrophils, enhanced cytotoxicity of CD56dim NK cells, and increased immune responsiveness of cDC2 and pDC, while inhibited maturation of plasmablasts and suppressed immune responsiveness of CD8{square}TEM and CD4+ T cells. Plasma metabolic analysis reveals significant alterations, involving enhanced steroid hormone synthesis, unsaturated fatty acid and amino acid metabolism under LTHAE, which in turn are associated with immune remodeling. Moreover, transcriptomic-metabolic integration analysis indicates the molecular mechanisms of enhanced aerobic oxidation efficiency under LTHAE. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.

genomics↗

bioRxiv2025

Genomic Evidence for Males of Exceptional Reproductive Output (ERO) in Apes and Humans

It is widely suspected that a small percentage of males have exceptional reproductive output (ERO) but progeny numbers of males are rarely measurable, even in humans. If we define the variance ratio of reproductive-output in males and females as = VM/VF, the ERO hypothesis would predict >>1. Since autosomal, X, and Y chromosomes are found in males 1/2, 1/3, and 100% of the time, their DNA diversities can inform about . For example, autosomal and Y-linked diversities are governed, respectively, by (VM+VF)/2 and VM. When comparing the chromosomal diversities, appears to be near 20 for chimpanzees and orangutans, and 1-10 for gorillas. The exception is bonobos with < 1. In humans, the extensive genomic data are coupled to a theory, developed herein, that can filter out selection influences on Y-linked diversities. Hence, the estimation of is rigorous, yielding values near or above 20, depending on the population. When >10, the presence of ERO males is very likely. These analyses can be applied more generally to species with XY sex determination.

evolutionary biology↗

bioRxiv2025

Senescent mast cells contribute to the progression of benign prostatic hyperplasia via SCF/c-KIT mediated endothelial-mesenchymal transition

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo. Thus, these findings revealed a senescence-linked immune-stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.

cell biology↗

bioRxiv2025

FEDRANN: effective overlap graph construction based on dimensionality reduction and approximate nearest neighbors

Overlap detection is a key step in de novo genome assembly pipelines based on the Overlap-Layout-Consensus (OLC) paradigm. However, existing methods for overlap detection either rely on heuristic seed-and-extension strategies or locality-sensitive hashing (LSH), both of which struggle to handle repetitive genomic regions and the computational burden of large-scale datasets. Here, we present FEDRANN, a novel strategy for overlap graph construction that integrates feature extraction, dimensionality reduction (DR), and approximate nearest neighbor (ANN) search. We find the pipeline combining inverse document frequency (IDF) transformation, sparse random projection (SRP), and NNDescent enables accurate detection of overlaps across diverse datasets. We developed an efficient open-source implementation of this pipeline named Fedrann (https://github.com/jzhang-dev/fedrann). Through systematic benchmarking on real long-read sequencing data, we demonstrate that Fedrann produces overlap graphs comparable to or better than those generated by existing state-of-the-art tools, including MECAT2, minimap2, and wtdbg2, while maintaining competitive runtime. Despite being implemented primarily in Python, Fedrann achieves performance on par with tools written in compiled languages, owing to matrix-based representations and C-accelerated numerical libraries. Our results suggest that DR and ANN techniques offer a promising new direction for scalable and accurate overlap detection in long-read assembly and broader sequence similarity search tasks.

bioinformatics↗

bioRxiv2025

Drosophila Metaxin-2 controls beta-barrel biogenesis and muscle growth in a stage-dependent fashion

Metaxin-2 (Mtx2) is an evolutionarily conserved mitochondrial outer membrane protein. Mutations in human Mtx2 cause mandibuloacral dysplasia (MADaM), a progeroid disorder. However, the pathologic mechanisms of Mtx2 loss-of-function remain largely unknown. Using Drosophila, we show Mtx2 null mutants exhibit pupal lethality, rescued by Drosophila or human Mtx2, underscoring functional conservation across species. Tissue-specific conditional knockout and rescue experiments reveal muscle as a critical site of dMtx2 action, with alternations of myofibril assembly and myogenic proteins being observed in dMtx2 mutants. Structural and functional mitochondrial abnormalities are also detected, verifying dMtx2s function in mitochondrial homeostasis. Notably, Mtx2 deficiency affects beta-barrel protein biogenesis and muscle development in pupa but not in larva, demonstrating Mtx2s dynamic regulation in mitochondrial proteostasis and muscle development. Our results elucidate mitochondrial mechanisms driving potential muscle-autonomous defects in MADaM patients and highlights stage-specific Mtx2 function as a prospective therapeutic target for this progeroid syndrome.

developmental biology↗

bioRxiv2025

ChromMovie: A Molecular Dynamics Approach for Simultaneous Modeling of Chromatin Conformation Changes from Multiple Single-Cell Hi-C Maps

The development of 3C-based techniques for analyzing three-dimensional chromatin structure dynamics has driven significant interest in computational methods for 3D chromatin reconstruction. In particular, models based on Hi-C and its single-cell variants, such as scHi-C, have gained widespread popularity. Current approaches for reconstructing the chromatin structure from scHi-C data typically operate by processing one scHi-C map at a time, generating a corresponding 3D chromatin structure as output. Here, we introduce an alternative approach to the whole genome 3D chromatin structure reconstruction that builds upon existing methods while incorporating the broader context of dynamic cellular processes, such as the cell cycle or cell maturation. Our approach integrates scHi-C contact data with single-cell trajectory information and is based on applying simultaneous modeling of a number of cells ordered along the progression of a given cellular process. The approach is able to successfully recreate known nuclear structures while simultaneously achieving smooth, continuous changes in chromatin structure throughout the cell cycle trajectory. Although both Hi-C-based chromatin reconstruction and cellular trajectory inference are well-developed fields, little effort has been made to bridge the gap between them. To address this, we present ChromMovie, a comprehensive molecular dynamics framework for modeling 3D chromatin structure changes in the context of cellular trajectories. To our knowledge, no existing method effectively leverages both the variability of single-cell Hi-C data and explicit information from estimated cellular trajectories, such as cell cycle progression, to improve chromatin structure reconstruction.

bioinformatics↗

bioRxiv2025

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3- producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

cancer biology↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

Optimizing electrode placement and information capacity for local field potentials in cortex

Recent neurosurgery advancements include improved stereotactic targeting and increased density and specificity of electrophysiological evaluation. This study introduces a subject-specific, in silico modeling tool for optimizing electrode placement and maximizing coverage with a variety of devices. The basis for optimization is the Shannon-Hartley information capacity of field potentials derived from dipolar sources. The approach integrates subject-specific MRI data with finite element modeling (FEM) used to simulate the sensitivity of subdural and intracortical devices. Sensitivity maps, or lead fields, from these models enable the comparison of different electrode placements, contact sizes, contact configurations, and substrate properties, which are often overlooked factors. One key tool is a genetic algorithm that optimizes electrode placement by maximizing information capacity. Another is a sparse sensor method, Sparse Electrode Placement for Input Optimization (SEPIO), that selects the best sensor subsets for accurate source classification. We demonstrate several use cases for clinicians, engineers, and researchers. Overall, these open-source tools provide a quantitative framework to select devices from a neurosurgical armament and to optimize device and contact placement. Using these tools may help refine electrode coverage with low channel count devices while minimizing the burden of invasive surgery. The study demonstrates that optimized electrode placement significantly improves the information capacity and signal quality of local field potential (LFP) recordings. The tools developed offer a valuable approach for refining neurosurgical techniques and enhancing the design of neural implants. HighlightsO_LItool for simulating subject-specific local field potentials and electrode sensitivity. C_LIO_LIptimized electrode placement enhances ROI source coverage, and signal quality. C_LIO_LIsensor-based classification boosts data quality without extra electrode cost. C_LIO_LIcomparisons of devices and contact arrangements. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/650658v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a3a7aaorg.highwire.dtl.DTLVardef@154a776org.highwire.dtl.DTLVardef@be4826org.highwire.dtl.DTLVardef@72caa9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity

Due to the inevitable progression to castration-resistant prostate cancer (CRPC) following treatment with androgen deprivation therapy (ADT), it is essential to develop novel treatment approaches for managing CRPC. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-{beta}1 to activate TGF-{beta} signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-{beta} signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-{beta} signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.

cancer biology↗

bioRxiv2024

An integrated view of the structure and function of the human 4D nucleome

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.

genomics↗