Biology subjects

Yao, X.

Publications and source records attributed to Yao, X..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Heterozygosity for Crohn's Disease Risk Allele of ATG16L1 Protects against Bacterial Infection

The T300A substitution in ATG16L1 associated with Crohns Disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300Adisplayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence. One-Sentence SummaryHeterozygosity of Crohns diseases risk variant ATG16L1 T300A confers protection against bacterial infections.

immunology↗

bioRxiv2024

The EGF/EGFR-YAP1/TEAD2 axis-mediated BRAF inhibitor vemurafenib resistance upregulates STIM1 in melanoma

STIM1 is the endoplasmic reticulum (ER) Ca2+ sensor for store-operated entry (SOCE) and closely correlated to carcinogenesis and tumor progression. Previously we found that STIM1 is upregulated in melanoma cells resistant to the BRAF inhibitor vemurafenib, but the regulation mechanism is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an EGF/EGFR-YAP1/TEAD2 axis. Vemurafenib resistance can lead to the increase of EGF and EGFR levels to activate the EGFR signaling pathway. Reactivated EGFR signal promotes YAP1 nuclear localization to increase the expression of STIM1. Our finding not only demonstrates the mechanism by which vemurafenib resistance promotes STIM1 expression, but also provides combined targeting EGF/EGFR-YAP1/TEAD2-STIM1 to improve the therapeutic efficiency of BRAF inhibitor in melanoma patients.

cancer biology↗

bioRxiv2024

TEMINET: A Co-Informative and Trustworthy Multi-Omics Integration Network for Diagnostic Prediction

Advancing the domain of biomedical investigation, integrated multi-omics data have shown exceptional performance in elucidating complex human diseases. However, as the variety of omics information expands, precisely perceiving the informativeness of intra- and inter-omics becomes challenging due to the intricate interrelations, thus posing significant obstacles in multi-omics data integration. To address this, we introduce a novel multi-omics integration approach, referred to as TEMINET. This approach enhances diagnostic prediction by leveraging an intra-omics co-informative representation method and a trustworthy learning strategy used to address inter-omics fusion. Considering the multifactorial nature of complex diseases, TEMINET utilizes intra-omics features to construct disease-specific networks, then applies graph attention networks and a multi-level framework to capture more collective informativeness than pairwise relations. To perceive the contribution of co-informative representations within intra-omics, we design a trustworthy learning strategy to identify the reliability of each omics in integration. To integrate inter-omics information, a combined beliefs fusion approach is deployed to harmonize the trustworthy representations of different omics types effectively. Our experiments across four different diseases using mRNA, methylation, and miRNA data demonstrate that TEMINET achieves advanced performance and robustness in classification tasks.

bioinformatics↗

bioRxiv2024

Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase

DNA base editors could enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here, by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants, we developed a deaminase-free glycosylase-based thymine base editor (gTBE) with the ability of direct T editing. By several rounds of UNG mutagenesis via rational screening, we demonstrated that gTBE with engineered UNG variants could achieve T editing efficiency by up to 81.5%. Furthermore, the gTBE exhibited high T-to-S (i.e., T-to-C or T-to-G) conversion ratio with up to 0.97 in cultured human cells. Using similar strategy, we developed a deaminase-free cytosine base editor (gCBE) facilitating specifically direct C editing by engineered UNG with mutations different from gTBE. Thus, we provide two novel base editors, gTBE and gCBE, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

molecular biology↗

bioRxiv2023

High-throughput structure determination of an intrinsically disordered protein using cell-free protein crystallization

Intrinsically disordered proteins (IDPs) play a crucial role in various biological phenomena, dynamically changing their conformations in response to external environmental cues. To gain a deeper understanding of these proteins, it is essential to identify the determinants that fix their structures at the atomic level. Here, we developed a pipeline for rapid crystal structure analysis of IDP using a cell-free protein crystallization (CFPC) method. Through this approach, we successfully demonstrated the determination of the structure of an IDP to uncover the key determinants that stabilize its conformation. Specifically, we focused on the 11-residue fragment of c-Myc, which forms an -helix through dimerization with a binding partner protein. This fragment was strategically fused with an in-cell crystallizing protein and was expressed in a cell-free system. The resulting crystal structures of the c-Myc fragment were successfully determined at a resolution of 1.92 [A] and we confirmed that they are identical to the structures of the complex with the native binding partner protein. This indicates that the environment of the scaffold crystal can fix the structure of c-Myc. Significantly, these crystals were obtained directly from a small reaction mixture (30 L) incubated for only 72 hours. Analysis of 8 crystal structures derived from 22 mutants revealed two hydrophobic residues as the key determinants responsible for stabilizing the -helical structure. These findings underscore the power of our CFPC screening method as a valuable tool for determining the structures of challenging target proteins and elucidating the essential molecular interactions that govern their stability.

biophysics↗

bioRxiv2023

Epiregulon: Inference of single-cell transcription factor activity to dissect mechanisms of lineage plasticity and drug response

Transcription factors (TFs) and transcriptional coregulators represent an emerging class of therapeutic targets in oncology. Gene regulatory networks (GRNs) can be used to evaluate pharmacological agents targeting these factors and to identify drivers of disease and drug resistance. However, GRN methods that rely solely on gene expression often fail to account for post-transcriptional modulation of TF function. We present Epiregulon, a method that constructs GRNs from single-cell ATAC-seq and RNA-seq data for accurate prediction of TF activity. This is achieved by considering the co-occurrence of TF expression and chromatin accessibility at TF binding sites in each cell. We leverage ChIP-seq data to extend inference to transcriptional coregulators lacking defined motifs or TF harboring neomorphic mutations. Epiregulon accurately predicted the effects of AR inhibition across various drug modalities including an AR antagonist and an AR degrader, delineated the mechanisms of a SMARCA4 degrader by identifying context-dependent interaction partners and prioritized known and novel drivers of lineage reprogramming and tumorigenesis. By mapping gene regulation across various cellular contexts, Epiregulon can accelerate the discovery of therapeutics targeting transcriptional regulators.

bioinformatics↗

bioRxiv2023

The mitochondrial deoxyguanosine kinase is required for female fertility in mice

Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleoside in the mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. Dguok loss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. We found that Dguok knockout results in female infertility. Mechanistically, the deficiency of DGUOK hinders ovarian development and oocyte maturation. Moreover, Dguok deficiency in oocytes caused a significant reduction in mitochondrial DNA and abnormal mitochondrial dynamics, and impaired germinal vesicle breakdown. Only few DGUOK-deficient oocytes were able to extrude the first polar body during in vitro maturation, and these oocytes showed irregular chromosome arrangement and different spindle lengths. In addition, Dguok deficiency elevated reactive oxygen species and accelerated apoptosis in oocytes. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate that DGUOK is a potential marker for the diagnosis of female infertility.

cell biology↗

bioRxiv2023

Detecting significantly recurrent genomic connections from simple and complex rearrangements in the cancer genome

The detection of somatic genetic alterations that recur across cancer genomes more than expected by chance has been a major goal of cancer genomics, as these alterations are enriched for "driver" events that promote cancer. Multiple methods have been developed to detect driver point mutations and copy-number variants, but methods to detect driver rearrangements have largely not been pursued. Unlike point mutations and copy-number alterations, which can be assigned to a single genomic locus, rearrangements connect two distant genomic loci, and possibly more in the case of complex or clustered events. Here, we explore genomic features that predict the rate at which any pair of loci will be connected by rearrangements and describe two methods to detect rearrangements that recur more often than this background rate. The first, SVSig-2D, detects pairs of loci that are directly connected by a single rearrangement; the second, SVSig-2Dc also detects loci that are recurrently connected indirectly through two or more rearrangements. When applied to a pan-cancer dataset of over 2,500 cancers, these methods identified 80 significantly recurrent simple rearrangements and 29 complex rearrangements, including both known and novel events. Intriguingly, though both recurrent simple and complex rearrangements tended to be tissue-specific, this was less true for the complex events. The detection of recurrent rearrangements with methods such as these will be an essential component of cancer genomics in the whole-genome sequencing era.

genomics↗

bioRxiv2023

Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway in human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability in cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination is dependent on the TEAD PARylation state. We further validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster. Despite the RNF146 and proteasome-mediated degradation mechanisms, TEADs are stable proteins with a long half-life in cells. We demonstrate that degradation of TEADs can be greatly enhanced pharmacologically with heterobifunctional chemical inducers of protein degradation (CIDEs). These TEAD-CIDEs can effectively suppress activation of YAP/TAZ target genes in a dose-dependent manner and exhibit significant anti-proliferative effects in YAP/TAZ-dependent tumor cells, thus phenocopying the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates that the ubiquitin-proteasome system plays an important role in regulating TEAD functions and provides a proof-of-concept demonstration that pharmacologically induced TEAD ubiquitination could be leveraged to target YAP/TAZ-driven cancers.

cancer biology↗

bioRxiv2023

A telomere-to-telomere genome assembly of Zhonghuang 13, a widely-grown soybean variety from the original center of Glycine max

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present the first Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar "Zhonghuang 13" (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

plant biology↗

bioRxiv2023

A muscle hypertrophy-derived myokine reprograms the stromal vascular fractions differentiation towards thermogenic adipocytes in subcutaneous adipose tissue

Skeletal muscle plays a significant role in both local and systemic energy metabolism; however, the cross-talk between skeletal muscle and adipose tissue remains largely unexplored. In this study, we identify the HIF2-Bambi-Thbs4 axis as a critical driver of muscle hypertrophy and metabolic improvement. Deletion of Bambi induces muscle hypertrophy and oxidative switching, thereby enhancing local and systemic metabolism under conditions of rodent chow and high-fat diets (HFD). Other than the metabolic regulation of skeletal muscle hypertrophy, we hypothesize that a portion of this improvement may be attributed to the metabolic reprogramming of the stromal vascular fraction (SVFs) of iWAT, promoting the development of beige adipocytes. Leveraging multi-omics approaches, we establish Thbs4 as a newly identified, muscle hypertrophy-derived myokine that serves as an essential regulator of this metabolic reprogramming. Thbs4 is upregulated in skeletal muscle during hypertrophy and aerobic exercise, localizes to the iWAT membrane, and facilitates the transformation of white adipocytes into beige adipocytes under conditions such as cold exposure, muscle hypertrophy, or aerobic exercise. Moreover, overexpression of Thbs4 elevates its plasma levels and leads to the transformation of white to beige adipocytes, therefore offering long-term protection against HFD-induced metabolic disorders. Conversely, Thbs4 knockout (Thbs4-KO) disrupts the metabolic reprogramming of SVFs and exacerbates metabolic syndromes induced by an HFD, mirroring the observed decline in Thbs4 levels in aged mice. Therefore, our findings underscore Thbs4s potential as both a long-term metabolic protective factor and a therapeutic target for the treatment of metabolic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/558627v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1178e6org.highwire.dtl.DTLVardef@1184d4eorg.highwire.dtl.DTLVardef@7b592aorg.highwire.dtl.DTLVardef@1b0b03_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBambi, a direct target gene of HIF2 in skeletal muscle, when deleted, triggers muscle hypertrophy and the transformation of white into beige adipocytes, improving systemic energy metabolism. C_LIO_LIThe metabolic reprogramming of stromal vascular fractions (SVFs) contributes to the observed improvements in energy metabolism and adipocyte hyperplasia. C_LIO_LIThbs4, a novel myokine produced in skeletal muscle during hypertrophy and aerobic exercise, plays a key role in the transformation of white into beige adipocytes. C_LIO_LIOverexpression of Thbs4 provides enduring protection against high-fat diet (HFD)-induced metabolic disorders, demonstrating its potential as a therapeutic target. C_LIO_LIThbs4 deletion abrogates the beneficial metabolic reprogramming of SVFs and exacerbates HFD-induced metabolic syndromes, further underlining its crucial role in metabolic regulation. C_LI

physiology↗

bioRxiv2023

OsNAC2 maintains the homeostasis of immune responses to bacterial blight through the OsEREBP1 in rice

Rice bacterial blight, caused by Xanthomonas oryzae pv. Oryzae (Xoo), threatens plant growth and yield. However, the molecular mechanisms underlying rice immunity against Xoo remain elusive. Here, we demonstrated down-regulation of a NAC (NAM-ATAF-CUC) transcription factor OsNAC2 enhanced resistance to bacterial blight disease in rice. Consistently, salicylic acid (SA) biosynthesis was greatly attenuated when OsNAC2 overexpressed. Furthermore, study demonstrated that OsNAC2 can down-regulated the expression of SA synthesis genes, thus mediating SA signal transmission. Simultaneously, OsNAC2 interacted with OsEREBP1 (AP2/ERF family) in the nucleus, may be bloking the inhibition of OsNAC2 to OsICS1, OsPAL3 and so on. Furthermore, OsEREBP1 interacted with OsXb22a in the cytoplasm to exert its positive regulatory effects to bacterial blight. However, OsNAC2-overexpression kept OsEREBP1 in the nucleus and be rapidly degraded in pathogen infection, which adversely affects the interaction of OsEREBP1-OsXb22a. Our results determined that OsNAC2 inhibits the SA signaling and stably interacts with OsEREBP1 to maintain disease resistance. This OsNAC2-OsEREBP1-based homeostatic mechanism provides new insights into rice disease resistance, and it may be useful for improving the disease resistance of important crops through breeding.

molecular biology↗

bioRxiv2023

A versatile framework for drug-target interaction prediction by considering domain specific features

Predicting drug-target interaction (DTI) is a critical and rate-limiting step in drug discovery. Traditional wet-lab experiments are reliable but expensive and time-consuming. Recently, deep learning has revealed itself as a new and promising tool for accelerating the DTI prediction process because its powerful performance. Due to the vast chemical space, the DTI prediction models are typically expected to discover drugs or targets that are absent from the training set. However, generalizing prediction performance to novel drug-target pairs that belong to different distributions is a challenge for deep learning methods. In this work, we propose an Ensemble of models that capture both Domain-generIc and domain-Specific features (E-DIS) to learn diversity domain features and adapt to out-of-distribution (OOD) data. We employed Mixture-of-Experts (MOE) as a domain-specific feature extractor for the raw data to prevent the loss of any crucial features by the encoder during the learning process. Multiple experts are trained on different domains to capture and align domain-specific information from various distributions without accessing any data from unseen domains. We evaluate our approach using four benchmark datasets under both in-domain and cross-domain settings and compare it with advanced approaches for solving OOD generalization problems. The results demonstrate that E-DIS effectively improves the robustness and generalizability of DTI prediction models by incorporating diversity domain features.

bioinformatics↗

bioRxiv2023

Oral immunization with rVSV bivalent vaccine elicits protective immune responses, including ADCC, against both SARS-CoV-2 and Influenza A viruses

COVID-19 and influenza both cause enormous disease burdens, and vaccines are the primary measures for their control. Since these viral diseases are transmitted through the mucosal surface of the respiratory tract, developing an effective and convenient mucosal vaccine should be a high priority. We previously reported a recombinant vesicular stomatitis virus (rVSV)-based bivalent vaccine (v-EM2/SP{Delta}C1Delta) that protects animals from both SARS-CoV-2 and influenza viruses via intramuscular and intranasal immunization. Here, we further investigated the immune response induced by oral immunization with this vaccine and its protective efficacy in mice. The results demonstrated that the oral cavity delivery, like the intranasal route, elicited strong and protective systemic immune responses against SARS-CoV-2 and influenza A virus. This included high levels of neutralizing antibodies (NAbs) against SARS-CoV-2, as well as strong anti-SARS-CoV-2 spike protein (SP) antibody-dependent cellular cytotoxicity (ADCC) and anti-influenza M2 ADCC responses in mice sera. Furthermore, it provided efficient protection against challenge with influenza H1N1 virus in a mouse model, with a 100% survival rate and a significant low lung viral load of influenza virus. All these findings provide substantial evidence for the effectiveness of oral immunization with the rVSV bivalent vaccine.

microbiology↗

bioRxiv2023

SRSF1-mediated alternative splicing of Tial1/Tiar is essential for homing and self-renewal in mouse spermatogonial stem cells

AbstractSpermatogonial stem cells (SSCs) are essential for continuous spermatogenesis and male fertility. The underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Crosslinking immunoprecipitation and sequencing (CLIP-seq) data revealed that spermatogonia-related genes (e.g., Plzf, Id4, Setdb1, Stra8, Tial1/Tiar, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Specific deletion of Srsf1 in mouse germ cells impairs homing of precursor SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult conditional knockout (cKO) mice, which indicates Sertoli cell-only syndrome (SCOS) in cKO mice. The expression of spermatogonia-related genes (Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of cKO mice. Moreover, multiomics analysis suggests that SRSF1 may affect survival of spermatogonia by directly binding and regulating Tial1/Tiar expression through AS. In addition, immunoprecipitation mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) data showed that SRSF1 interacts with RNA splicing-related proteins (SART1, RBM15, and SRSF10). Collectively, our data reveal the critical role of SRSF1 in spermatogonia survival, which may provide a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying homing of precursor SSCs.

developmental biology↗

bioRxiv2023

A KDELR-mediated ER retrieval system guides the signaling pathways of UPR and AMPK to maintain cellular homeostasis

KDELR (Erd2 in yeasts) mediates the retrieval of ER-resident proteins from the Golgi apparatus, yet how the KDELR-mediated ER retrieval system is involved in regulating cellular homeostasis has been unclear. Here we report that the loss of the Erd2-mediated ER retrieval system induces the unfolded protein response (UPR) and increases mitochondrial respiration and reactive oxygen species (ROS) in an UPR-dependent manner. Moreover, transcriptomic analysis revealed that expression of the genes involved in mitochondrial respiration and the tricarboxylic acid cycle is enhanced in an UPR-dependent manner in cells lacking Erd2. In cells lacking Erd2, the enhancement of mitochondrial respiration and ROS is required for maintaining cell viability. The loss of the Erd2-mediated ER retrieval system also activates AMPK, and consequently derepresses carbon catabolite repression. Hence, our work establishes a role of the KDELR/Erd2-mediated ER retrieval system in guiding the signalling pathways of AMPK and UPR and underscores the crucial role of the KDELR/Erd2-mediated ER retrieval system in the maintenance of cellular homeostasis.

cell biology↗

bioRxiv2023

cProSite: A web based interactive platform for online proteomics, phosphoproteomics, and genomics data analysis

We developed cProSite, a website that provides online genomics, proteomics, and phosphoproteomics analysis for the data of The National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC). This tool focuses on comparisons and correlations between different proteins and mRNAs of tumors and normal tissues. Our website is designed with biologists and clinicians in mind, with a user-friendly environment and fast search engine. The search results of cProSite can be used for clinical data validation and provide useful strategic information to identify drug targets at proteomic, phosphoproteomic, or genomic levels. The site is available at http://cprosite.ccr.cancer.gov. SignificanceAn interactive database for the expression and correlation for proteins, proteomic phosphorylations, and mRNA levels has been developed for analyzing the molecular alterations between tumors and normal tissues of various tumor types.

bioinformatics↗

bioRxiv2023

Spatiotemporal transcriptome atlas of human embryos after gastrulation

The spatial and temporal atlas of gene expression in the human embryo at early gestation is critical in understanding embryo development, organogenesis, and disease origins. We obtained the spatiotemporal transcriptome from 90 sagittal sections of 16 whole human embryos from 3 to 8 post-conception weeks by Stereo-seq with high resolution and ultra-large field, establishing the development trajectory/regulatory profiling of 49 organs. We uncovered the organ-specific regulons as potential lineage-determining factors and identified the new regulatory networks during heart and brain development. The atlas refines the key organs/cell types vulnerable to virus infection and genetic disorders, and, reveals the dynamics of allelic gene expression in specific organs at different stages. These results present the first comprehensive delineation of the spatiotemporal transcriptomic dynamics of human organogenesis. One Sentence SummaryThe spatiotemporal transcriptome atlas presents a comprehensive delineation of human embryogenesis after gastrulation.

developmental biology↗