Biology subjects

Yang, Z.

Publications and source records attributed to Yang, Z..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 235 primary human cartilage samples. We identified 3,352 independent significant expression quantitative trait loci (eQTLs) for 3,109 genes. We explored the candidate casual SNP and its underlying regulatory mechanism using our established functional fine-mapping pipeline by integrating the cartilage-specific ATAC-seq data. We identified 117 causal eQTLs that display allele-specific open chromatin (ASoC) and 547 transcription factor binding-disruption (TBD) eQTLs. We conducted cell type-interaction eQTL (ci-eQTL) analyses based on speculated chondrocyte subtype proportions and revealed the regulation relationship of 120 eQTL-gene pairs showed cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 43 candidate effector genes for OA risk loci. We verified that the T allele of the OA risk variant rs11750646 increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related gene PIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.

genetics↗

bioRxiv2024

The Role of ADGRA3 in Adipose Thermogenesis: A Potential Therapeutic Target for Obesity

The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. {beta}3-adrenoceptor ({beta}3-AR) is widely recognized as a canonical {beta}-adrenergic G protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of {beta}3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown of Adgra3 resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers. Conversely, Adgra3 overexpression activated the adipose thermogenic program and improved metabolic homeostasis without an exogenous ligand supplementation. We found that ADGRA3 facilitates the biogenesis of beige adipocytes through the Gs-PKA-CREB axis. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selectively overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.

cell biology↗

bioRxiv2024

Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.

microbiology↗

bioRxiv2024

Stearoyl coenzyme A desaturase 1 (SCD1) regulates foot-and-mouth disease virus replication by modulating host cell lipid metabolism and 2C-mediated replication complex formation

The life cycle of foot-and-mouth disease virus (FMDV) is tightly regulated by host cell lipid metabolism. In a previous study, we successfully established a BHK-21 cell model (BHK-Op) for persistent FMDV infection by single-cell clone selection and isolated a virus-negative cell line (BHK-VEC cells) from high-passage BHK-Op cells. BHK-VEC cells could be not infected with FMDV. By conforming the transcriptome data of BHK-VEC cells and BHK-21 cells, we identified that the stearoyl coenzyme A desaturase 1 (SCD1), a key enzyme for the fatty acid metabolism, regulates FMDV replication. SCD1 overexpression or exogenous addition of oleic acid (OA), a product of SCD1 enzyme activity, promoted or upregulated FMDV replication in BHK-21 cells or SCD1 knockdown cells, respectively. Interestingly, overexpression of SCD1 or exogenous addition of OA restored the FMDV infection and replication in BHK-VEC cells. Exogenous addition of OA also promoted FMDV replication in BHK-Op. SCD1 recruited the nonstructural FMDV protein 2C to the detergent-resistant membrane located in the perinuclear nucleus to form replication complex. Inhibition of SCD1 enzyme activity resulted in significantly decreased number of FMDV replication complexes with also abnormal morphology. Importantly, inhibition of SCD1 enzyme activity effectively suppressed replication of other positive-sense RNA viruses, such as REO176, PV1 and EV71. Our results demonstrated that, as a key host regulator of RNA virus replication, SCD1 is a potential target for developing novel drugs against positive-sense RNA virus infection.

microbiology↗

bioRxiv2024

iResNetDM: Interpretable deep learning approach for four types of DNA modification prediction

MotivationDespite the development of several computational methods to predict DNA modifications, two main limitations persist in the current methodologies: 1) All existing models are confined to binary predictor which merely determine the presence or absence of DNA modifications, constraining comprehensive analyses of the interrelations among varied modification types. While multi-class classification models for RNA modifications have been developed, a comparable approach for DNA remains a critical need. 2) The majority of previous studies lack adequate explanations of how models make decisions, relying on the extraction and visualization of attention matrices which identified few motifs, and do not provide sufficient insight into the model decision making process. ResultIn this study, we introduce iResNetDM, a deep learning model that integrates ResNet and self-attention mechanisms. To the best of our knowledge, iResNetDM is the first model capable of distinguishing between four types of DNA modifications. It not only demonstrates high performance across various DNA modifications but also unveils the potential capabilities of CNN and ResNet in this domain. To augment the interpretability of our model, we implemented the integrated gradients technique, which was pivotal in demystifying the models decision-making framework, allowing for the successful identification of multiple motifs. Importantly, our model exhibits remarkable robustness, successfully identifying unique motifs across different modifications. Furthermore, we compared the motifs discovered in various modifications, revealing that some motifs share significant sequence similarities which suggests that these motifs may be subjected to different types of modifications, underscoring their potential importance in gene regulation. Contactzeruiyang2-c@my.cityu.edu.hk

bioinformatics↗

bioRxiv2024

Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs

The tRNA methyltransferase 1 (TRMT1) enzyme catalyzes m2,2G modification in tRNAs. Intriguingly, vertebrates encode an additional tRNA methyltransferase 1-like (TRMT1L) paralog. Here, we use a comprehensive tRNA sequencing approach to decipher targets of human TRMT1 and TRMT1L. We find that TRMT1 methylates all known tRNAs containing guanosine at position 26 while TRMT1L represents the elusive enzyme catalyzing m2,2G at position 27 in tyrosine tRNAs. Surprisingly, TRMT1L is also necessary for maintaining acp3U modifications in a subset of tRNAs through a process that can be uncoupled from methyltransferase activity. We also demonstrate that tyrosine and serine tRNAs are dependent upon m2,2G modifications for their stability and function in translation. Notably, human patient cells with disease-associated TRMT1 variants exhibit reduced levels of tyrosine and serine tRNAs. These findings uncover unexpected roles for TRMT1 paralogs, decipher functions for m2,2G modifications, and pinpoint tRNAs dysregulated in human disorders caused by tRNA modification deficiency.

molecular biology↗

bioRxiv2024

Pseudomonas syringae socially-induced swimming motility requires the molybdenum cofactor

Social interactions among bacteria can induce behaviors that affect their fitness and influence how complex communities assemble. Here we report a new socially-induced motility behavior that we refer to as baited expansion in Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), a plant pathogenic bacterium. We found Pst DC3000 displayed strongly-induced swimming motility towards nearby colonies of Dickeya dianthicola or Escherichia coli. We developed a controlled system to visualize and characterize the development of baited expansion. Our results provide evidence that baited expansion behavior occurs in response to a chemical gradient established and maintained by the bait colony. We also found this behavior correlated with distinct transcriptional profiles and identified molybdenum cofactor as a crucial factor in facilitating the baited expansion behavior.

microbiology↗

bioRxiv2024

In Search of the Perfect Model: How Cancer Cell Lines Relate to Native Cancers

Cancer cell lines are frequently used in biological and translational research to study cellular mechanisms and explore treatment options. However, cancer cell lines may display mutational profiles divergent from native cancers or may be misidentified or contaminated. We explored how similar cancer cell lines are to native cancers to find the most suitable representations for the corresponding diseases by utilising large collections of copy number variation (CNV) profiles and applied machine learning (ML) algorithms to predict cell line classifications. Our results confirm that cancer cell lines indeed accumulate more mutations compared to native cancers but retain similar CNV profiles. We demonstrate that many relevant oncogenes and tumor suppressor genes are altered by CNV events in both cancers and their corresponding cell lines. Based on the similarities between the two groups and the predictions of the ML model, we provide some recommendations about cell lines with good potential to represent selected cancer types in in vitro studies.

cancer biology↗

bioRxiv2024

A foundation model for generalizable cancer diagnosis and survival prediction from histopathological images

Computational pathology, utilizing whole slide image (WSI) for pathological diagnosis, has advanced the development of intelligent healthcare. However, the scarcity of annotated data and histological differences hinder the general application of existing methods. Extensive histopathological data and the robustness of self-supervised models in small-scale data demonstrate promising prospects for developing foundation pathology models. Due to the need for deployment, lightweight foundation models also need to be developed. In this work, we propose the BEPH (BEiT-based model Pre-training on Histopathological images), a general lightweight foundation model that leverages self-supervised learning to learn meaningful representations from 11 million unlabeled histopathological images. These representations are then efficiently adapted to various tasks, including 2 cancer patch-level recognition tasks, 3 cancer WSI-level classification tasks, and 6 cancer subtypes survival prediction tasks. Experimental results demonstrate that our model consistently outperforms several comparative models with similar parameters, even with limited training data reduced to 50%. Especially when the downstream structure is the same, the model can improve ResNet and DINO by up to a maximum increase of 8.8% and 7.2% (WSI level classification), and 6.44% and 3.28% on average (survival prediction), respectively. Therefore, BEPH offers a universal solution to enhance model performance, reduce the burden of expert annotations, and enable widespread clinical applications of artificial intelligence. The code and models can be obtained at https://github.com/Zhcyoung/BEPH. And currently, online fine-tuning of WSI classification tasks is available for use on http://yulab-sjtu.natapp1.cc/BEPH.

pathology↗

bioRxiv2024

Epigenetic delineation of the earliest cardiac lineage segregation by single-cell multi-omics

The mammalian heart is formed from multiple mesoderm-derived cell lineages. However, it remains largely unknown when and how the specification of mesoderm towards cardiac lineages is determined. Here, we systematically depict the transcriptional trajectories toward cardiomyocyte in early mouse embryo, and characterize the epigenetic landscapes underlying the early mesodermal lineage specification by single-cell multi-omics analyses. The analyses also reveal distinct core regulatory networks (CRN) in controlling specification of mesodermal lineages. We further demonstrate the essential role HAND1 and FOXF1 in driving the earliest cardiac progenitors specification. These key transcription factors occupy at distinct enhancers, but function synergistically and hierarchically to regulate the expression of cardiac-specific genes. In addition, HAND1 is required for exiting from the nascent mesoderm program, while FOXF1 is essential for driving cardiac differentiation during juxta-cardiac field (JCF) specification. Our findings establish transcriptional and epigenetic determinants specifying the early cardiac lineage, providing insights for the investigation of congenital heart defects.

molecular biology↗

bioRxiv2024

Inference of continuous gene flow between species under misspecified models

Gene flow between species is increasingly recognized as an important evolutionary process with potential adaptive consequences. Recent methodological advances make it possible to infer different modes of gene flow from genome-scale data, including pulse introgression at a specific time and continuous gene flow over an extended time period. However, it remains challenging to infer the history of species divergence and between-species gene flow from genomic sequence data. As a result, models used in real data analysis may often be misspecified, potentially leading to incorrect biological interpretations. Here, we characterize biases in parameter estimation under continuous migration models using a combination of asymptotic analysis and posterior inference from simulated datasets. When sequence data are generated under a pulse introgression model, isolation-with-initial-migration models assuming no recent gene flow are able to better recover gene flow with less bias than models that assume recent gene flow. When gene flow is assigned to an incorrect branch in the phylogeny, there may be large biases associated with the migration rate and species divergence times. When the direction of gene flow is incorrectly assumed, we may still detect gene flow if it is recent and between non-sister species but not when it is ancestral and between sister species. Overall, the impact of model misspecification is local in the species phylogeny. The pulse introgression model appears to be more robust to model misspecification and is preferable in real data analysis over the continuous migration model unless there is substantive evidence for continuous gene flow.

evolutionary biology↗

bioRxiv2024

Silybin B, resveratrol and epigallocatechin-3 gallate (EGCG) bind to troponin to restore the loss of lusitropy caused by cardiomyopathy mutations in vitro, in vivo, and in silico

Adrenergic activation of protein kinase A (PKA) targets the thin filaments of the cardiac muscle, specifically phosphorylating cTroponin I Ser22 and Ser23, causing a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate (lusitropy). This modulation is often suppressed by mutations that cause cardiomyopathy (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of relaxation rate could have the potential for treatment of these pathologies. We found, using single thin filament in vitro motility assays that the small molecules including silybin B, resveratrol, and epigallocatechin-3 gallate (EGCG) can restore coupling. We performed molecular dynamics simulations of the unphosphorylated and phosphorylated cardiac Troponin core with the TNNC1 G159D mutation. We found that silybin B, EGCG, and resveratrol restored the phosphorylation-induced change in the TnC helix A/B angle and the interdomain angle to wild-type values, whilst silybin A and epicatechin gallate (ECG) did not. In unphosphorylated G159D the recoupling molecules were observed to be frequently intercalated between The N terminal peptide of Troponin I and troponin C. In contrast, the controls, silybin A, and ECG bound to the surface. All of the interactions were diminished when troponin I was phosphorylated. We also performed studies with intact transgenic ACTC E99K mouse cells and TNNT2 R92Q-transfected guinea pig cardiomyocytes. The mutations blunt the increase in relaxation speed due to dobutamine; resveratrol, EGCG, and silybin B could restore the dobutamine response whilst silybin A did not. Thus recoupling by small molecules is demonstrated in vitro, in vivo, and in silico.

biophysics↗

bioRxiv2024

Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2

Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular schwannomas, spinal schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

developmental biology↗

bioRxiv2024

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

cancer biology↗

bioRxiv2024

Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states

Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists--a limitation that restricts understanding of the functional NR conformational ensemble. Here, we report a NR ligand series for peroxisome proliferator-activated receptor gamma (PPAR{gamma}) that spans a pharmacological spectrum from repression (inverse agonism) to activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots of the fully repressive state, NMR spectroscopy and conformation-activity relationship analysis reveals that compounds within the series shift the PPAR{gamma} conformational ensemble between transcriptionally active and repressive conformations that are populated in the apo/ligand-free ensemble. Our findings reveal a molecular framework for minimal chemical modifications that enhance PPAR{gamma} inverse agonism and elucidate their influence on the dynamic PPAR{gamma} conformational ensemble.

biophysics↗

bioRxiv2024

A 3D atlas of sexually dimorphic lumbosacral motor neurons that control and integrate pelvic visceral and somatic functions in rats

The lumbosacral spinal motor system comprises somatic motor neurons (SMNs) that target striated muscle and visceral motor neurons (VMNs; autonomic preganglionic neurons) that target peripheral ganglia. The brain coordinates these pathways to mediate functions such as continence, voiding and sexual function by ensuring appropriate changes of organ state with striated muscle activity (e.g., sphincter opening, relevant postural changes). These spinal circuits are important therapeutic targets for bioelectronic medicine yet are poorly defined in comparison with limb SMNs. We aimed to define the structural features and relationships between SMNs and VMNs relevant to pelvic function in male and female rats, by building 3D maps of lumbosacral spinal cord. We achieved this by applying large-volume immunostaining (choline acetyltransferase), with tissue clearing and advanced whole mount microscopy (light sheet and ribbon scanning confocal microscopy). We identified VMNs specific to pelvic organ function by microinjecting cholera toxin (beta-subunit) into the major pelvic ganglia (MPG). These VMNS are primarily located in segments L1-L2 (dorsal commissural nucleus) and L6-S1 (intermediolateral nucleus). Unexpectedly, small groups of SMNs in the urethral rhabdosphincter, cremaster and levator ani motor pools also projected through the MPG. Motor neuron counts and analysis of dendritic fields detected sexual dimorphism in both SMNs and VMNs. Their colocation of dendritic bundles suggested a mechanism of coordinating activity. This study has provided the first multiscale 3D atlas of rat lumbosacral cord. This will be shared as a resource on an open science platform (sparc.science) to allow further exploration and modeling of network features and cellular morphology.

neuroscience↗

bioRxiv2024

A high-continuity and annotated reference genome of allotetraploid Siberian wildrye (Elymus sibiricus L., Poaceae: Triticeae)

Elymus sibiricus L. (Siberian wildrye, Es), a species belonging to the wheat tribe, is extensively employed as forage and for the reclamation of degraded grasslands within the Qinghai-Tibet Plateau (QTP). This study provides a high-quality reference genome assembly for the allotetraploid Es, which is composed of 14 pseudomolecules with the total genome size of 6.57 Gb. Our finding suggest that large-scale bursts of retrotransposons are critical for the genome expansion of Es. We discovered a translocation event between the Es4H and Es6H chromosomes with a low frequency of combination. Phylogenetic analyses of 90 Es accessions and 25 diploid accessions representing proposed ancestors from various habitats revealed the existence of four distinct populations. We further provided support for the hypothesis that the QTP is the center of origin and genetic diversity for Es. Collectively, our study offers valuable insights into the evolution of Es, as well as providing genomic resources for genetic enhancement in the Elymus genus and wheat tribe.

genomics↗

bioRxiv2024

Spirolactone, an unprecedented antifungal β-lactone spiroketal macrolide from Streptomyces iranensis

Fungal infections pose a great threat to public health and there are limited antifungal medicaments. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. The rapamycin-producer Streptomyces iranensis harbors an unparalleled Type I polyketide synthase, which codes for a novel antifungal macrolide alligamycin A (1), the structure of which was confirmed by NMR, MS, and X-ray crystallography. Alligamycin A harbors an undescribed carbon skeleton with 13 chiral centers, featuring a ({beta}-lactone moiety, a [6,6]-spiroketal ring, and an unprecedented 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential novel crotonyl-CoA carboxylase/reductase. The ali biosynthetic gene cluster was confirmed through CRISPR-based gene editing. Alligamycin A displayed profound antifungal effects against numerous clinically relevant filamentous fungi, including Talaromyces and Aspergillus species. ({beta}-Lactone ring is essential for the antifungal activity and alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupted the integrity of fungal cell walls and induced the expression of stress-response proteins in Aspergillus niger. Alligamycins represent a new class of potential drug candidate to combat fungal infections.

biochemistry↗