Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 757 records · Page 42Linked to original sources

bioRxiv2022

HCP5 prevents ubiquitination-mediated UTP3 degradation to inhibit apoptosis by activating c-Myc transcriptional activity

Inducing cancer cell apoptosis through cytotoxic reagents is the main therapeutic strategy for diverse cancer types. However, several antiapoptotic factors impede curative cancer therapy by driving cancer cells to resist cytotoxic agent-induced apoptosis, thus leading to refractoriness and relapse. To define critical antiapoptotic factors that contribute to chemoresistance in esophageal squamous cell carcinoma (ESCC), we generated two pairs of parental and apoptosis-resistant cell models through cisplatin (DDP) induction and then performed whole-transcriptome sequencing. We identified the long noncoding RNA (lncRNA) histocompatibility leukocyte antigen complex P5 (HCP5) as the chief culprit for chemoresistance. Mechanistically, HCP5 interacts with UTP3 small subunit processome component (UTP3) and prevents UTP3 degradation from E3 ligase tripartite motif containing 29 (TRIM29)-mediated ubiquitination. UTP3 then recruits c-Myc to activate vesicle-associated membrane protein 3 (VAMP3) expression. Activated VAMP3 suppresses caspase-dependent apoptosis and eventually leads to chemoresistance. Accordingly, the expression level of the HCP5/UTP3/c-Myc/VAMP3 axis in chemoresistant patients is significantly higher than that in chemosensitive patients. Thus, our study demonstrated that the HCP5/UTP3/c-Myc/VAMP3 axis plays an important role in the inhibition of cancer cell apoptosis and that HCP5 can be a promising chemosensitive target for cancer treatment.

cancer biology↗

bioRxiv2022

Metabolic control of histone acetylation for precise and timely regulation of minor ZGA in early mammalian embryos

Metabolism feeds into the regulation of epigenetics via metabolic enzymes and metabolites. However, metabolic features, and their impact on epigenetic remodeling during mammalian pre-implantation development, remain poorly understood. In this study, we established the metabolic landscape of mouse pre-implantation embryos from zygote to blastocyst, and quantified some absolute carbohydrate metabolites. We integrated these data with transcriptomic and proteomic data, and discovered the metabolic characteristics of the development process, including the activation of methionine cycle from 8-cell embryo to blastocyst, high glutaminolysis metabolism at blastocyst stage, enhanced TCA cycle activity from the 8-cell embryo stage, and active glycolysis in the blastocyst. We further demonstrated that oxidized nicotinamide adenine dinucleotide (NAD+) synthesis is indispensable for mouse pre-implantation development. Mechanistically, in part, NAD+ is required for the exit of minor zygotic gene activation (ZGA) by cooperating with SIRT1 to remove zygotic H3K27ac. In human, NAD+ supplement can promote the removal of zygotic H3K27ac and benefit pre-implantation development. Our findings demonstrate that precise and timely regulation of minor ZGA is controlled by metabolic dynamics, and enhance our understanding of the metabolism of mammalian early embryos. HighlightsO_LIWe identified the metabolic features of mouse pre-implantation embryo development. C_LIO_LINAD+ synthesis is indispensable for mouse embryo pre-implantation development. C_LIO_LINAD+-mediated erasure of zygotic H3K27ac is required for the exit of minor ZGA. C_LIO_LINAD+ supplement promotes the removal of zygotic H3K27ac and benefits preimplantation development of human embryos. C_LI

developmental biology↗

bioRxiv2022

Tracking infectious entry routes of SARS-CoV-2

SARS-CoV-2 cell entry starts with membrane attachment and ends with spike-protein (S) catalyzed membrane fusion depending on two cleavage steps, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time 3D single virion tracking, we show fusion and genome penetration requires virion exposure to an acidic milieu of pH 6.2-6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2 overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2 expressing cells in the acidic milieu of the nasal cavity. Significance StatementInfection by SARS-CoV-2 depends upon the S large spike protein decorating the virions and is responsible for receptor engagement and subsequent fusion of viral and cellular membranes allowing release of virion contents into the cell. Using new single particle imaging tools, to visualize and track the successive steps from virion attachment to fusion, combined with chemical and genetic perturbations of the cells, we provide the first direct evidence for the cellular uptake routes of productive infection in multiple cell types and their dependence on proteolysis of S by cell surface or endosomal proteases. We show that fusion and content release always require the acidic environment from endosomes, preceded by liberation of the S1 fragment which depends on ACE2 receptor engagement. One sentence summaryDetailed molecular snapshots of the productive infectious entry pathway of SARS-CoV-2 into cells

microbiology↗

bioRxiv2022

Single-cell Multi-omics Integration for Unpaired Data by a Siamese Network with Graph-based Contrastive Loss

Single-cell omics technology is being rapidly developed to measure the epigenome, genome, and transcriptome across a range of cell types. However, integrating omics data from different modalities is still challenging. Here, we propose a variation of the Siamese neural network framework called MinNet, which is trained to integrate multi-omics data on the single-cell resolution by utilizing graph-based contrastive loss. By training the model and testing it on several benchmark datasets, we showed its accuracy and generalizability in integrating scRNA-seq with scATAC-seq, and scRNA-seq with epitopes data. Further evaluation demonstrated our models unique capacity in removing the batch effect, which is a common problem in actual practice. To show how the integration impacts downstream analysis, we established model-based smoothing and cis-regulatory element inferring method and validated it with external pcHi-C evidence. Finally, the framework was applied to a COVID-19 dataset to compensate the original work with integration-based analysis, showing its necessity in single-cell multi-omics research.

bioinformatics↗

bioRxiv2022

Population Sequencing Reveals Rht-D1b Contributing the Bigger Seedling Root to Modern Wheat Cultivars

The Green Revolution (GR) has dramatically increased the yield of modern wheat cultivars; however, whether and how GR reshaped the wheat root system remains largely unknown. Here, a large-scale transcriptomic and phenotypical investigation was performed on seedling roots of 406 worldwide bread wheat accessions, showing differential transcriptomes and phenotypes between landrace and modern cultivars, and the GR allele Rht-D1b was the main genetic factor driving this phenotype differential, conferring a significantly larger seedling root to modern cultivars by increasing cell length and root meristem size. In this case, the translational reinitiation of TaRht-D1 underlies Rht-D1bs genetic effects. In contrast, another GR allele, Rht-B1b, has no significant effects on root-related traits, differing from the similar genetic effects of these two GR alleles on reducing plant height. This unexpected effect of Rht-D1b on root systems contributes to a substantially larger root-shoot ratio in modern wheat cultivars. These findings reveal previously overlooked benefits of GR alleles in modern wheat cultivars and provide clues for their future application to form a robust seminal root system.

plant biology↗

bioRxiv2022

Spatially Resolved Metabolites in Stable and Vulnerable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging

Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core. Atherosclerotic tissue specimens were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging (MSI) on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and HMDB, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheroma. We then integrated these results with an RNA-sequencing dataset comparing stable and unstable human atherosclerosis. Upon integrating our MSI results with the RNA-seq dataset, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. Acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindole-acetic acid was enriched in the fibrous cap. Our work herein represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/494038v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@111368org.highwire.dtl.DTLVardef@1112d99org.highwire.dtl.DTLVardef@c8cdb2org.highwire.dtl.DTLVardef@13895d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2022

Gene expression and RNA splicing explain large proportions of the heritability for complex traits in cattle

Many quantitative trait loci (QTL) are located in non-coding genomic regions. Therefore, QTL are assumed to affect gene regulation. Gene expression and RNA splicing are primary steps of transcription so QTL changing gene expression (eQTL) or RNA splicing (sQTL) are expected to significantly contribute to phenotypic variations. Here, we quantify the contribution of eQTL and sQTL detected from 16 tissues (N~5,000) to 37 complex traits of ~120k cattle. Using Bayesian methods, we show that including more regulatory variants in the model explains larger proportions of heritability. Across traits, cis and trans eQTL and sQTL detected from 16 tissues jointly explain ~70% (SE=0.5%) of heritability, 44% more than expected from the same number of random variants, where trans e/sQTL contribute 24% (14% more than expected). Multi-tissue cis and trans e/sQTL also explain 71% (SE=0.3%) of heritability for the metabolome, demonstrating the essential role of proximal and distal regulatory variants in shaping mammalian phenotypes.

genomics↗

bioRxiv2022

Plasticity-induced actin polymerization in the dendritic shaft regulates intracellular AMPA receptor trafficking

AMPA-type receptors (AMPARs) are rapidly inserted into synapses undergoing long-term potentiation (LTP) to increase synaptic transmission, but how AMPAR-containing vesicles are selectively trafficked to these synapses during LTP is not known. Here we developed a strategy to label AMPAR GluA1 subunits expressed from the endogenous loci of rat hippocampal neurons such that the motion of GluA1-containing vesicles in time-lapse sequences can be characterized using single-particle tracking and mathematical modeling. We find that GluA1- containing vesicles are confined and concentrated near sites of stimulation-induced plasticity. We show that confinement is mediated by actin polymerization, which hinders the active transport of GluA1-containing vesicles along the length of the dendritic shaft by modulating the rheological properties of the cytoplasm. Actin polymerization also facilitates myosin-mediated transport of GluA1-containing vesicles to exocytic sites. We conclude that neurons utilize F- actin to increase vesicular GluA1 reservoirs and promote exocytosis proximal to the sites of neuronal activity.

neuroscience↗

bioRxiv2022

CspZ FH-binding sites as epitopes promote antibody-mediated Lyme borreliae clearance

Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato (Bbsl) is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. Bbsl produces the CspZ protein that binds to the complement inhibitor, Factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from Bb infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly-and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) more efficiently eliminate Bbsl in vitro than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH binding site antibodies eradicated Bbsl in vivo. Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against Bbsl in future LD vaccines.

immunology↗

bioRxiv2022

Lineage-Specific Differences and Regulatory Networks Governing Human Chondrocyte Development

To address large gaps in our understanding of the molecular regulation of articular and growth plate cartilage development in humans, we used our directed differentiation approach to generate these distinct cartilage tissues from human embryonic stem cells. The resulting transcriptomic profiles of hESC-derived articular and growth plate chondrocytes were similar to fetal epiphyseal and growth plate chondrocytes, with respect to genes both known and previously unknown to cartilage biology. With the goal to characterize the regulatory landscapes accompanying these respective transcriptomes, we mapped chromatin accessibility in hESC-derived chondrocyte lineages, and mouse embryonic chondrocytes, using ATAC-sequencing. Integration of the expression dataset with the differentially accessible genomic regions revealed lineage-specific gene regulatory networks. We validated functional interactions of two transcription factors (RUNX2 in growth plate chondrocytes and RELA in articular chondrocytes) with their predicted genomic targets. The maps we provide thus represent a framework for probing regulatory interactions governing chondrocyte differentiation. This work constitutes a substantial step towards comprehensive and comparative molecular characterizations of distinct chondrogenic lineages, and sheds new light on human cartilage development and biology.

developmental biology↗

bioRxiv2022

A "cooperative collaboration" between HAND2 and MYCN shapes neuroblastoma cell identity

Noradrenergic neuroblastoma (NB) is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TFs) such as PHOX2B, HAND2 and GATA3, which form a network with MYCN. Physiological levels of MYCN mainly binds to promoters but aberrantly upregulated MYCN in NB also binds to enhancers. How MYCN invades enhancers, and what role the CRC TFs play in this process is unknown. Here we find that HAND2 assists MYCN to invade enhancers through an "indirect cooperative" TF-DNA binding mechanism. HAND2 cooperates with MYCN to compete with nucleosomes and regulate global gene transcription. The treatment of NB with an Aurora A kinase inhibitor plus HDAC inhibitor potently downregulates both MYCN and the CRC TFs and suppresses MYCN-amplified NB tumor growth. Our study identifies a "cooperative collaboration" among MYCN and CRC TFs and the simultaneous targeting these TFs is an effective way to treat this aggressive pediatric tumor.

cancer biology↗

bioRxiv2022

Comprehensive machine-learning survival framework develop a consensus model in large scale multi-center cohorts for pancreatic cancer

BackgroundAs the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. MethodsA total of 1280 patients from 10 multi-center cohorts were enrolled. 10 machine-learning algorithms were transformed into 76 combinations, which were performed to construct an artificial intelligence-derived prognostic signature (AIDPS). The predictive performance, multi-omic alterations, immune landscape, and clinical significance of AIDPS were further explored. ResultsBased on 10 independent cohorts, we screened 32 consensus prognostic genes via univariate Cox regression. According to the criterion with the largest average C-index in the nine validation sets, we selected the optimal algorithm to construct the AIDPS. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the 9-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, relatively high frequency of mutations and copy number alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Correspondingly, the high AIDPS group possessed dramatically prolonged survival, and panobinostat might be a potential agent for patients with high AIDPS. ConclusionsThe AIDPS could accurately predict the prognosis and immunotherapy efficacy of PACA, which might become an attractive tool to further guide the stratified management and individualized treatment. FundingThis study was supported by the National Natural Science Foundation of China (No. 81870457, 82172944).

bioinformatics↗

bioRxiv2022

Intermittent fasting mitigates cognitive deficits in Alzheimer's disease via the gut-brain axis

Intermittent fasting (IF) is suggested to mitigate cognitive impairment in Alzheimers disease (AD). We detailed the effects of IF in AD development and assessed the contribution of the gut microbiota-metabolite-brain axis in promoting the effects of fasting. A 16-week IF regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by decreased A{beta} accumulation and suppression of neuroinflammation. IF reshaped the microbiota and beneficially altered the microbial metabolites related to cognitive function. Multi-OMICs integration demonstrated a strong connection between IF induced changes in hippocampus gene expression, the composition of the gut microbes, and the serum metabolites beneficial for cognitive function. Removal of gut microbes with antibiotics abolished the neuroprotective effects of IF. These findings suggest new avenues for therapy and nutritional intervention to prevent the development of AD and other neurodegenerative diseases.

animal behavior and cognition↗

bioRxiv2022

VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer

Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-{beta} pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-{beta} signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) and a competing endogenous RNA (ceRNA) to sponge miR-22-5p/514a-3p to increase the translation of TGF-{beta}, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-{beta}/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.

cancer biology↗

bioRxiv2022

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.

immunology↗

bioRxiv2022

Soil nitrogen impacts the rhizosphere microbial community owing to microbial hitchhiking

Microbial hitchhiking demonstrates that some nonmotile microbes utilize trans-species motility to traverse their environment; however, whether driving forces, such as plants and nitrogen, affect microbial hitchhiking is not clear. In our study, we explored the effects of plants and nitrogen fertilizer on Bacillus-hitchhiking by setting filter membranes and different nitrogen fertilizer concentration gradients. In the experimental treatment, we added a filter membrane to the soil to prevent hitchhiking. In the absence of plants, nitrogen alone had little influence on motile bacteria and hitchhiking. However, Bacillus contents were significantly impacted by the nitrogen concentration when the plants were rooted, leading to a great variation in cell motility function according to the functional analysis in the soil microbial community. After applying the filter membrane, there were no significant differences in Bacillus contents, microbial community structure or cell motility functional abundance, which illustrated that hitchhiking impacted the microbial community. Our analysis of co-occurrence between bulk soil motile bacteria (Bacillus) and rhizosphere bacteria also confirmed this. The correlation between bulk soil motile bacteria and the rhizosphere microbial community was strong in the groups with suitable nitrogen concentrations without filter membranes and was weak at all nitrogen levels in the no-membrane treatments. Thus, we concluded that plants and different nitrogen doses synergistically altered the soil microbiome by hitchhiking, whose effect depends on nitrogen.

microbiology↗

bioRxiv2022

Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace

Tissues are highly complicated with spatial heterogeneity in gene expression. However, the cutting-edge single-cell RNA-seq technology eliminates the spatial information of individual cells, which contributes to the characterization of cell identities. Herein, we propose single-cell spatial position associated co-embeddings (scSpace), an integrative algorithm to distinguish spatially variable cell subclusters by reconstructing cells onto a pseudo-space with spatial transcriptome references (Visium, STARmap, Slide-seq, etc.). We demonstrated that scSpace can define biologically meaningful cell subpopulations neglected by single-cell RNA-seq or spatially resolved transcriptomics. The use of scSpace to uncover the spatial association within single-cell data, reproduced, the hierarchical distribution of cells in the brain cortex and liver lobules, and the regional variation of cells in heart ventricles and the intestinal villus. scSpace identified cell subclusters in intratelencephalic neurons, which were confirmed by their biomarkers. The application of scSpace in melanoma and Covid-19 exhibited a broad prospect in the discovery of spatial therapeutic markers.

bioinformatics↗

bioRxiv2022

Tbx2 is essential for cochlear inner hair cell development and regeneration

Atoh1 is essential for the development of outer hair cells (OHCs) and inner hair cells (IHCs) in the mammalian cochlea. Whereas Ikzf2 is necessary for OHC development, the key gene for IHC development remains unknown. We found that deleting Tbx2 in neonatal IHCs led to their trans-differentiation into OHCs, by repressing 26.7% of IHC and inducing 56.3% of OHC genes, including Ikzf2. More importantly, persistent expression of Tbx2 together with transient Atoh1 effectively reprogramed non-sensory supporting cells into new IHCs expressing functional IHC marker vGlut3. The differentiation status of these new IHCs is much more advanced than those previously reported. Thus, Tbx2 is essential for IHC development, and its co-upregulation with Atoh1 in supporting cells represents a new approach for treating IHC degeneration-related deafness.

developmental biology↗