Biology subjects

Yu, C.

Publications and source records attributed to Yu, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Loss of Ythdf3 causes Danon disease-like features

YTH domain-containing family (YTHDF1/2/3) recognizes m6A modified mRNAs and regulates their stability, translation and function. We found loss of Ythdf3 in mice caused cardiac hypotrophy, myopathy, and intellectual abnormalities, resembling the clinical features of a rare inherited X-linked disorder Danon disease (DD). Mechanistically, this was attributable to the compromised mRNA decay of sex-determining region Y (SRY)-box 9 (Sox9), mediated by YTHDF3 m6A reader function. Targeted therapy with AAV-shRNA against Sox9 ameliorated fibrosis, increased neuron number, and significantly improved heart and brain function in Ythdf3-/- mice. Our data reveal that loss of murine Ythdf3 recapitulates systemic DD-like features, attributable to impaired Sox9 decay, and highlight a novel therapeutic target for DD.

molecular biology↗

bioRxiv2025

Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor

NOTCH3 variants cause CADASIL the most common genetic form of small vessel disease (SVD) and vascular dementia (VaD) and increase the stroke and SVD/VaD risk. CADASIL is a systemic vasculopathy but predominantly manifests in the brain. The molecular mechanisms of CADASIL remain largely unclear with no specific available treatments. NOTCH3 is primarily expressed in vascular smooth muscle cells (VSMCs). Using human induced pluripotent stem cell (iPSC) models and developmental lineage-specific VSMC differentiation, we revealed a selective vulnerability of cerebral but not peripheral VSMC mimics to NOTCH3 variants. Transcriptomic, protein and functional analyses demonstrated a switching of CADASIL iPSC-VSMCs from a contractile to a synthetic phenotype, accompanied with extensive extracellular matrix accumulation and impairment of cell adhesion leading to anoikis. Importantly, we describe an endothelial independent nitric oxide signalling in VSMCs which was dysregulated in the CADASIL iPSC-VSMCs, and posphodiesterase-5 (PDE5) inhibition successfully rescued the abnormal VSMC function, suggesting a novel therapeutic strategy. Our findings offer new mechanistic insights into brain specific phenotype in NOTCH3-associated SVD/VaD and support patient-specific iPSCs to be a valuable model for identifying targeted treatment for NOTCH3-associated SVD/VaD.

neuroscience↗

bioRxiv2025

Behavioral Time Scale Synaptic Plasticity (BTSP) endows Hyperdimensional Computing with attractor features

Human reasoning depends on reusing pieces of information by binding them together in new ways, thereby "making infinite uses of finite means" (Alexander von Humboldt). Needed for that is a binding mechanism that enables fast composition and decomposition of tokens of information. Binding can easily be implemented in symbolic computations through parentheses and ordering of symbols. But it is a highly nontrivial operation for distributed representations, where the tokens are encoded by activity patterns in large neural networks or large language models, or more abstractly, by a high dimensional vector. Vector Symbolic Architectures (VSAs) provide partial solutions, but are lacking the flexibility of the brain in information retrieval, e.g. retrieving the tokens from a composed representation or retrieval of a composed representation by just providing some tokens as a cue. We show that a mechanism which the brain employs for binding distributed representations, Behavioral Time Scale Synaptic Plasticity (BTSP), overcomes these deficiencies. In particular, it combines binding with attractor features that make information retrieval substantially more flexible and robust. We evaluate its performance on various applications, including encoding and decoding complex visual scenes and hierarchical binding. We also show that it enhances models for natural language processing and abstract brain computation. BTSP-based binding only requires binary synaptic weights and simple local synaptic plasticity, and can therefore easily be implemented through in-memory computing or other innovative designs for energy-efficient AI implementations.

animal behavior and cognition↗

bioRxiv2025

Aird-MSI: a high compression rate and decompression speed format for mass spectrometry imaging data

Mass spectrometry imaging has emerged as a pivotal tool in spatial metabolomics, yet its reliance on the imzML format poses critical challenges in data storage, transmission, and computational efficiency. While imzML ensures cross-platform compatibility, its lower compressed binary architecture results in large file sizes and high parsing overhead, hindering cloud-based analysis and real-time visualization. This study introduces an enhanced Aird compression format optimized for spatial metabolomics through two innovations: (1) a dynamic combinatorial compression algorithm for integer-based encoding of m/z and intensity data; (2) a coordinate-separation storage strategy for rapid spatial indexing. Experimental validation on 47 public datasets demonstrated significant performance gains. Compared to imzML, Aird achieved a 70% reduction in storage footprint (mean compression ratio: 30.03%) while maintaining near-lossless data precision (F1-score = 99.26% at 0.1 ppm m/z tolerance). For high-precision-controlled datasets, Aird accelerated loading speeds by 15-fold in MZmine. The Aird format overcomes crucial bottlenecks in spatial metabolomics by harmonizing storage efficiency, computational speed, and analytical precision, reducing I/O latency for large cohorts. By achieving near-native feature detection accuracy, Aird establishes a robust infrastructure for translational applications, including disease biomarker discovery and pharmacokinetic imaging.

bioinformatics↗

bioRxiv2025

Learning copy number dependent variation in single tumour cell transcriptomes with deep generative models

Large-scale copy number aberrations are a hallmark of many cancers, showing widespread associations with tumour cell phenotypes, therapy resistance, and patient outcomes. Several existing methods can infer copy number profiles from single-cell RNA-sequencing data. However, there is currently no methodology to separate the effects of the copy number state on single tumour cell phenotypes from the copy number-independent variation. We present ISOMERIC, an unsupervised deep learning framework to learn disentangled representations of single-cell expression data that are dependent on or independent of copy number profiles. We apply ISOMERIC to multiple cancer types and examine how copy number shapes transcriptional states. We find distinct associations between copy number-dependent and independent variation and clinical subtypes in multiple cancer types and link such variation to tumour microenvironment phenotypes. Together, this establishes a principled framework for untangling the effects of genetic and intrinsic variation on tumour transcriptomes and the consequences on clinically meaningful phenotypes.

bioinformatics↗

bioRxiv2025

Super Recombinator (SuRe): An in vivo recombination system for scalable and efficient transgene assembly at a single genomic locus

The capacity to engineer organisms with multiple transgenic components is crucial to synthetic biology and basic biology research. For the former field, transgenic organisms allow the creation of novel biological functions; for the latter, such organisms provide potent means of dissecting complex biological pathways. However, the size limitations of a single transgenesis event and challenges associated with the assembly of multiple DNA fragments hinder the efficient integration of multiple transgenes. To overcome these hurdles, here we introduce a building block for synthetic design termed an integrated genetic array (IGA), which incorporates all genetic components into a single locus to prevent their separation during genetic manipulations. Since the natural recombination rate for genes located in the same locus is near zero, to construct IGAs we developed the Super Recombinator (SuRe) system, which uses CRISPR/Cas9, alone or in combination with site-specific serine recombinases, for in vivo transgene recombination at a single genomic locus. SuRe effectively doubles the number of elements assembled in each recombination round, exponentially accelerating IGA construction. By preventing the separation of transgenic elements, SuRe greatly reduces screening burdens, as validated here through studies of Drosophila melanogaster and Caenorhabditis elegans. To optimize SuRe, we compared CRISPR/Cas9-induced homology-directed recombination to site-specific recombination using various serine recombinases. Optimized versions of SuRe achieved efficiency and fidelity values near their theoretical maxima and allowed the generation of recombinant products up to 4.2 Mbp in size in Drosophila. Using SuRe, we created fruit flies with 12 transgenic elements for fluorescence voltage imaging of neural activity in precisely defined cell-types. Mathematical modeling of the scalability of SuRe to large transgene assemblies showed that integration times and gene assembly workloads respectively scale logarithmically and linearly with the number of transgenes, both major improvements over conventional approaches. Overall, SuRe enables the efficient integration of multiple genes at individual loci, up to the chromosomal scale.

synthetic biology↗

bioRxiv2025

The GSA Family in 2025: A Broadened Sharing Platform for Multi-Omics and Multimodal Data

The Genome Sequence Archive Family (GSA family) provides a suite of database resources for archiving, retrieving, and sharing multi-omics data for the global academic and industrial communities. It currently comprises four distinct database members: the Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/gsa/), the Genome Sequence Archive for Human (GSA-Human, https://ngdc.cncb.ac.cn/gsa-human/), the open Archive for Miscellaneous Data (OMIX, https://ngdc.cncb.ac.cn/omix/), and the Open Biomedical Imaging Archive (OBIA, https://ngdc.cncb.ac.cn/obia). Compared to the 2021 version, the GSA family has significantly expanded by introducing a new database member, the OBIA, and through comprehensive upgrades to the existing ones. Notable enhancements to the existing members include broadening the range of accepted data types, enhancing the quality control systems, fine-tuning the data retrieval system, and refining the data-sharing management mechanisms.

genomics↗

bioRxiv2025

Human endogenous retrovirus K (HERV-K) envelope structures in pre- and post-fusion by Cryo-EM

The HERV-K envelope glycoprotein (Env) is aberrantly expressed in diseases including cancers and autoimmune disorders and is targeted by antibodies. The lack of structural information has hindered functional and immune recognition studies. We solved structures of the HERV-K Env in both pre- and post-fusion states with novel monoclonal antibodies using cryo-EM. The pre-fusion Env assembles as a trimer with a distinct fold and architecture compared to other retroviruses, while the post-fusion conformation features a unique "tether" helix within the TM subunit. A panel of monoclonal antibodies, elicited to facilitate structure determination, have been characterized for conformational and subunit specificity, serving as valuable research tools. These findings establish a structural framework for mechanistic studies of HERV-K Env in diseases and evaluation as a potential therapeutic target.

biochemistry↗

bioRxiv2025

AlphaFold3 and RoseTTAFold All-Atom structures enable radiosensitizers discovery by targeting multiple DNA damage repair proteins

Radioresistance remains a primary obstacle in tumor radiotherapy, with no clinically approved radiosensitizers due to toxicity concerns. To identify effective and safe radiosensitizers, a natural products database containing 79,263 compounds are docked against a hybrid target library of four DNA damage response (DDR)-related proteins, comprising both experimental and artificial intelligence (AI)-predicted structures generated by AlphaFold3 and RoseTTAFold All-Atom models. Retrospectively, AI-modeled structures show comparable AUC and logAUC values to experimental structures. Prospectively, compounds screened by AI-modeled structures versus those by experimental structures exhibit limited overlap, e.g., 10% for ataxia telangiectasia mutated (ATM), 22.2% for ATM- and Rad3-related (ATR), 7.7% for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and 40% for Poly (ADP-ribose) polymerase 1 (PARP1). This highlights structural complementarity of AI-modeled structures when docking against small-scale compound libraries. Two compounds exhibiting lower binding free energy than the DNA-PKcs co-crystallized ligand were selected and validated as effective radiosensitizers in tumor cells. Proteomic analyses reveal shared DDR dysregulation but distinct repair pathway vulnerabilities behind both compounds, which activate TP53-associated apoptosis and senescence as cellular endpoints by modulating the synergistic interplay between DDR and spindle checkpoints. These findings highlight their potential as context-dependent radiosensitizers, providing novel candidates and strategies to overcome tumor radioresistance.

cancer biology↗

bioRxiv2025

Nucleosome binding relinquishes the association of the BAH domain of Orc1 with Sir1

Mating-type switching in S. cerevisiae requires silencing of the homothallic mating (HM) loci through formation of position-dependent, gene-independent repressive chromatin domains, resembling heterochromatic regions in higher eukaryotes. Genetic and biochemical studies have identified cis-acting DNA elements, called silencers, and trans-acting protein factors important for the establishment and maintenance of the silent chromatin. Yet, the molecular mechanism governing the position-dependence of gene silencing is not fully understood. Here we report that the BAH domain of Orc1, which is responsible for recruiting Sir1 to the Orc1-bound silencers, ceases to bind Sir1 in the presence of nucleosome. This finding suggests a unified role of sensing the chromatin environment by Orc1s BAH domain in transcriptional silencing and specification of replication origins. We further dissected the structural determinants of the BAH domain required for binding Sir1. These results expanded the understanding of Orc1s functions in epigenetic silencing of the HM loci.

molecular biology↗

bioRxiv2025

Somatic repetitive element insertions Define New Biomarkers in Pan-cancer genome

Repetitive elements insertions (REIs), including tandem repeat insertions (TRIs) and transposable element insertions (TEIs), constitute >90% of large-scale (>50bp) somatic insertions and are linked to diseases and cancer biomarkers. However, the genomic landscape of large-scale REIs in pan-cancer has not been well-characterized due to short-read sequencing limitations. Here, we detected somatic REIs in 325 cancer genomes across 12 cancer types using long-read whole-genome sequencing and customized algorithms. The diverse sequence patterns of somatic TRIs and the insertion mechanisms of somatic TEIs were characterized across different cancer types. We identified 152 high-frequency somatic TRIs, with 10 showing pan-cancer characteristics, including TRIs in SHROOM2, PALMD, and the enhancer of PTPRZ1. The MHC class II gene cluster exhibited the highest somatic TEI abundance, affecting [~]40% tumors. Adenocarcinomas and squamous cell carcinomas exhibited differing TEI distributions within this region. Our study highlights REIs as important but under-explored markers for personalized cancer diagnosis and immunotherapy.

genomics↗

bioRxiv2025

Leopard Cats Occupied Human Settlements in China for 3,500 years before the Arrival of Domestic cats in 600-900 CE around the Tang Dynasty

The earliest cats in human settlements in China were not domestic cats (Felis catus), but native leopard cats (Prionailurus bengalensis). To trace when and how domestic cats arrived in East Asia, we analyzed 22 feline bones from 14 sites across China spanning 5,000 years. Nuclear and mitochondrial genomes revealed that leopard cats began occupying anthropogenic scenes around 5,400 years ago and last appeared in 150 CE. Following several centuries gap of archeological feline remains, the first known domestic cat (706-883 CE) in China was identified in Shaanxi during the Tang Dynasty. Genomic analysis suggested a white or partially white coat and a link to a contemporaneous domestic cat from Kazakhstan, indicating a likely dispersal route via the Silk Road. The two felids once independently occupied ancient anthropogenic environments in China but followed divergent paths and reached different destinations in human-animal interactions.

evolutionary biology↗

bioRxiv2025

Chronic degenerative failure of salivary glands can be reversed through restoring mitochondrial function

Chronic degenerative wounds are often deemed irreparable, directing research efforts to focus predominantly on acute tissue injury regeneration while leaving endogenous repair mechanisms for chronically damaged tissues largely unexplored. In this study, we demonstrate that non-healing, severely degenerated salivary gland tissues can be fundamentally restored through first-line treatment with muscarinic agonists. This approach rescues tissue structure and function, returning it to a homeostatic-like state, and reactivates endogenous regeneration processes to drive new cell expansion that persists for months post-treatment. Furthermore, neuromimetic activation profoundly depletes radiation-induced DNA damage and re-establishes the nerve-acinar relationship, ultimately restoring the tissues physiological capacity to maintain homeostasis, even in the absence of treatment. We show that full recovery of organ function, comparable to uninjured controls, is primarily mediated by the re-differentiation of aberrantly de-differentiated epithelial acinar cells and the restoration of mitochondrial function via a muscarinic-calcium signaling pathway. These findings challenge the prevailing notion that chronic organ degeneration is irreversible and propose a readily testable therapeutic strategy for epithelial restoration with potential applications across a spectrum of chronic injuries.

cell biology↗

bioRxiv2025

From experimental clues to theoretical modeling: Evolution associated with the membrane-takeover at an early stage of life

Modern cell membranes are primarily composed of phospholipids, while primitive cell membranes in the beginning of life are believed to have formed from simpler lipids (such as fatty acids) synthesized in the prebiotic environment. An attractive experimental study suggested that the corresponding "membrane-takeover" (as an evolutionary process) is likely to have occurred very early (e.g. in the RNA world) due to some simple physical effects, and might have subsequently triggered some other evolutionary processes. Here, via computer modeling on a system of RNA-based protocells, we convinced the plausibility of such a scenario and elaborated on relevant mechanisms. It is shown that in protocells with a fatty-acid membrane, because of the benefit of phospholipid content (i.e., stabilizing the membrane), a ribozyme favoring the synthesis of phospholipids may emerge; subsequently, due to the reduced membrane permeability on account of the phospholipid content, two other functional RNA species could arise: a ribozyme exploiting more fundamental materials (thus more permeable) for nucleotide synthesis and a species favoring across-membrane transportation. This case exemplifies a combination of experimental and theoretical efforts regarding early evolution, which may shed light on that notoriously complicated problem: the origin of life.

evolutionary biology↗

bioRxiv2024

Crosslinking-mediated Interactome Analysis Identified PHD2-HIF1α Interaction Hotspots and the Role of PHD2 in Regulating Protein Neddylation

Prolyl Hydroxylase Domain protein 2 (PHD2) targets Hypoxia Inducible Factor alpha subunits (HIF) for oxygen-dependent proline hydroxylation that leads to subsequent ubiquitination and degradation of HIF. In addition to HIF proteins, growing evidence suggested that PHD2 may exert its multifaceted function through hydroxylase-dependent or independent activities. Given the critical role of PHD2 in diverse biological processes, it is important to comprehensively identify potential PHD2 interacting proteins. In this study, we engineered HeLa cells that stably express HTBH-tagged PHD2 to facilitate the identification of PHD2 interactome. Using DSSO-based cross-linking mass spectrometry (XL-MS) technology and LC-MSn analysis, we mapped PHD2-HIF1 interaction hotspots and identified over 300 PHD2 interacting proteins. Furthermore, we validated the COP9 Signalosome (CSN) complex, a major deneddylase complex, as a novel PHD2 interactor. DMOG treatment promoted interaction between PHD2 and CSN complex and enhanced the deneddylase activity of the CSN complex, resulting in increased level of free Cullin and reduced target protein ubiquitination. This mechanism may serve as a negative feedback regulation of the HIF transcription pathway.

biochemistry↗

bioRxiv2024

Cellular behavior analysis from live-cell imaging of TCR T cell-cancer cell interactions

T cell therapies, such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cells, are a growing class of anti-cancer treatments. However, expansion to novel indications and beyond last-line treatment requires engineering cells dynamic population behaviors. Here we develop the tools for cellular behavior analysis of T cells from live-cell imaging, a common and inexpensive experimental setup used to evaluate engineered T cells. We first develop a state-of-the-art segmentation and tracking pipeline, Caliban, based on human-in-the-loop deep learning. We then build the Occident pipeline to collect a catalog of phenotypes that characterize cell populations, morphology, movement, and interactions in co-cultures of modified T cells and antigen-presenting tumor cells. We use Caliban and Occident to interrogate how interactions between T cells and cancer cells differ when beneficial knock-outs of RASA2 and CUL5 are introduced into TCR T cells. We apply spatiotemporal models to quantify T cell recruitment and proliferation after interactions with cancer cells. We discover that, compared to a safe harbor knockout control, RASA2 knockout T cells have longer interaction times with cancer cells leading to greater T cell activation and killing efficacy, while CUL5 knockout T cells have increased proliferation rates leading to greater numbers of T cells for hunting. Together, segmentation and tracking from Caliban and phenotype quantification from Occident enable cellular behavior analysis to better engineer T cell therapies for improved cancer treatment.

cell biology↗

bioRxiv2024

RNA methylation controls stress granule formation and function during erythropoiesis

Stress granules (SGs) are crucial in RNA regulation, affecting cell fate and function. SGs contain RNAs, some of which can be methylated. We studied m6A RNA modifications during the human CD34+ HSPCs (hCD34+) differentiating into erythroid cells and found that mRNAs encoding many erythroid-specific proteins had decreased methylation during differentiation. Increased levels ALKBH5 demethylase during erythropoiesis controls the levels of the 3UTR methylation of these mRNAs. hCD34+ carrying ALKBH5 mutations demonstrated a block in erythropoiesis, and mass-spectrometry studies of the mutant cells showed decreased levels of SG proteins, including the core granule protein ATXN2. ALKBH5 directly regulates the methylation of the mRNA of ATXN2. ATXN2 overexpression accelerated the erythroid differentiation of HSPCs and rescued the erythroid differentiation of ALKBH5 mutant cells. Very few SGs are found in normal human erythroid progenitors. SGs accumulated substantially in ALKBH5 mutant cells, and surprisingly overexpression of ATNX2 reduced SG numbers to normal. Polysome analysis demonstrated m6A-modified RNAs to be enriched in the pre-polysome fractions that were less translated. This work establishes a mechanism by which during stress, ATXN2 facilitates the release of SG-stored m6A-modified RNAs including erythroid-specific and SG-enriched RNAs that are loaded onto functional ribosomes, allowing better translation and accelerated erythroid differentiation during stress.

cell biology↗

bioRxiv2024

The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer's Disease

The gene signatures of Alzheimers Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulation., yet the dominant factor shaping these signatures remains unclear. To identify the most significant factor that shapes the AD brain signatures, we integrated cellular and molecular features with differential gene expression in in an explainable machine learning framework. Our result indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signatures. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking down and pharmacologically inhibiting YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulate the AD-associated transcriptional signatures. Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results highlight the central role of YTHDF proteins in shaping the gene signatures of AD brains.

neuroscience↗