Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 775 records · Page 43Linked to original sources

bioRxiv2022

Inhibition of c-Jun in AgRP neurons mediates chronic stress-induced anxiety-like behaviors and colitis susceptibility

Psychiatric disorders, such as anxiety, are frequently associated with inflammatory bowel diseases (IBD), however, the neural mechanisms are unknown. Here, we showed that hypothalamic agouti-related protein (AgRP) neuronal activity was suppressed under chronic restraint stress (CRS), a condition known to induce anxiety-like behaviors and increase colitis susceptibility. Consistently, chemogenic activation (inhibition) of AgRP neurons reversed (mimicked) CRS-induced anxiety-like behaviors and colitis susceptibility. Furthermore, CRS inhibited AgRP neuronal activity by suppressing the expression of c-Jun. As expected, overexpression of c-Jun in these neurons protected against the CRS-induced these effects and knockdown of c-Jun in AgRP neurons (c-Jun{Delta}AgRP) promoted anxiety-like behaviors and colitis. Moreover, relieving the anxiety with cyamemazine (an anxiolytic drug) alleviated colitis susceptibility in c-Jun{Delta}AgRP mice. Finally, according to a proteomic analysis, the levels of the secreted protein thrombospondin 1 (THBS1) were negatively associated with the increased anxiety-like behaviors and colitis susceptibility, supplementing recombinant THBS1 rescued colitis in c-Jun{Delta}AgRP mice. Taken together, these results reveal a critical role of hypothalamic AgRP neuron-derived c-Jun in orchestrating chronic stress-induced anxiety-like behaviors and colitis susceptibility. These results provide a new perspective for understanding the neuronal mechanisms and potential therapeutic target for the comorbidity of psychiatric disorders, such as anxiety, and IBD.

neuroscience↗

bioRxiv2022

Deep mutational scanning and machine learning reveal structural and molecular rules governing allosteric hotspots in homologous proteins

A fundamental question in protein science is where allosteric hotspots - residues critical for allosteric signaling - are located, and what properties differentiate them. We carried out deep mutational scanning (DMS) of four homologous bacterial allosteric transcription factors (aTF) to identify hotspots and built a machine learning model with this data to glean the structural and molecular properties of allosteric hotspots. We found hotspots to be distributed protein-wide rather than being restricted to "pathways" linking allosteric and active sites as is commonly assumed. Despite structural homology, the location of hotspots was not superimposable across the aTFs. However, common signatures emerged when comparing hotspots coincident with long-range interactions, suggesting that the allosteric mechanism is conserved among the homologs despite differences in molecular details. Machine learning with our large DMS datasets revealed that global structural and dynamic properties to be a strong predictor of whether a residue is a hotspot than local and physicochemical properties. Furthermore, a model trained on one protein can predict hotspots in a homolog. In summary, the overall allosteric mechanism is embedded in the structural fold of the aTF family, but the finer, molecular details are sequence-specific.

biochemistry↗

bioRxiv2022

Extensive diversity of RNA viruses in ticks revealed by metagenomics in northeastern China

Recently, several emerging tick-borne viruses have been identified to be associated with human diseases in northeastern China. Here, we used metagenomics to investigate the virome diversity in Haemaphysalis japonica, H. conicinna, Dermacentor silvarum, and Ixodes persulcatus ticks in northeastern China. A total of 22 RNA viruses were identified and belonged to more eight viral families, including four each in Nairoviridae and Phenuiviridae, three each in Flaviviridae, Rhabdoviridae, and Solemoviridae, two in Chuviridae, and one each in Partitiviridae, Tombusviridae, and unclassified. Of them, eight viruses were novel species, belonging to Nairoviridae (Jian nairovirus and Yichun nairovirus), Phenuiviridae (Mudanjiang phlebovirus), Rhabdoviridae (Tahe rhabdovirus 1-3), Chuviridae (Yichun mivirus), and Tombusviridae (Yichun tombus-like virus), and five members were established human pathogens, including Alongshan virus, tick-borne encephalitis virus, Songling virus, Beiji nairovirus, and Nuomin virus. I. persulcatus ticks had significant higher viral species than those in H. japonica, H. concinna, and D. silvarum ticks. Significant differences in tick viromes were observed among Daxingan, Xiaoxingan and Changbai mountains. These findings showed an extensive diversity of RNA viruses in ticks in northeastern China, revealed potential public health threats from the emerging tick-borne viruses. Further studies are needed to explain the natural circulation and pathogenicity of these viruses.

microbiology↗

bioRxiv2022

Identification of two bZIP transcription factors that regulate development of pavement and trichome cells in Arabidopsis thaliana by single-cell RNA-sequencing

Epidermal cells are the main avenue for signal and material exchange between plants and the environment. Leaf epidermal cells primarily include pavement cells (PCs), guard cells, and trichomes cells (TCs), which differentiate from protodermal cells or meristemoids. The development and distribution of different epidermal cells are tightly regulated by a complex transcriptional regulatory network mediated by phytohormones, including jasmonic acid (JA), and transcription factors. Understanding how the fate of leaf epidermal cells is determined, however, is still largely unknown due to the diversity of cell types and the complexity of its regulation. Here, we characterized the transcriptional profiles of epidermal cells in 3-day-old true leaves of Arabidopsis thaliana using single-cell RNA-sequencing. We identified two genes encoding BASIC LEUCINE-ZIPPER (bZIP) transcription factors, namely the bZIP25 and bZIP53, which are highly expressed in PCs and early-stage meristemoid cells. Densities of PCs and TCs were found to increase and decrease, respectively, in bzip25 and bzip53 mutants, compared with wild-type plants. This trend was more pronounced in the presence of JA, suggesting that these transcription factors regulate the development of TCs and PCs in response to JA. IN A NUTSHELLO_ST_ABSBackgroundC_ST_ABSLeaf epidermal cells, comprised of trichome cells (TCs), guard cells (GCs), and pavement cells (PCs), are responsible for exchanging materials and information between plants and the surrounding aerial environment. Many genes have been identified in Arabidopsis thaliana and confirmed to be involved in the initiation and differentiation of TCs and PCs. The fate determination of TCs and PCs is tightly regulated by positive and negative regulators at the cellular level. The precise underlying molecular mechanisms responsible for the fate determination of TCs and PCs, however, are still unclear at this time. QuestionWhat are the transcriptomic profiles of different leaf epidermal cell types? Can we dissect the genes that are specifically expressed in certain epidermal cell types? What kinds of transcription factors are involved in regulating the fate determination of TCs and PCs? FindingsWe performed single cell RNA-seq to investigate the transcriptomic profiles of different leaf epidermal cell types and identified differentially expressed genes in each cell type. We found that genes that are involved in jasmonic acid signaling are highly expressed in early-stage meristemoid (EM) cells which can act as the precursor of PCs and perhaps of TCs. To investigate the regulatory mechanisms underlying EM development, we identified the transcription factors (TFs) in EM cells and found that two bZIP TF genes, bZIP25 and bZIP53, are highly expressed in EMs. Further analyses of these two genes using both loss-of-function and gain-of-function approaches indicated that bZIP25 and bZIP53 are functionally involved in promoting trichome formation but inhibit pavement cell development in response to jasmonic acid. Next stepsBesides of bZIP25 and bZIP53, we also identified other key genes, for example FES1B, in leaf epidermal cells. Our next step will be to explore the regulation of other key genes involved in the fate determination of different cell types in leaf epidermis.

plant biology↗

bioRxiv2022

Population genomics unravels the Holocene history of Triticum-Aegilops species

Deep knowledge of crop biodiversity is essential to improve global food security. Despite bread wheat serving as a keystone crop worldwide, the population history of bread wheat and its wild relatives (a.k.a. wheats) remains elusive. By analyzing whole-genome sequences of 795 wheats, we found that bread wheat originated southwest of the Caspian Sea [~]11,700 years ago and underwent a slow speciation process, lasting [~]3,300 years due to persistent gene flow from wild relatives. Soon after, bread wheat spread across Eurasia and reached Europe, South Asia, and East Asia [~]7,000 to [~]5,000 years ago, shaping a diversified but occasionally convergent adaptive landscape of bread wheat in novel environments. Opposite to cultivated wheat, wild wheat populations have declined by [~]82% in the past [~]2,000 years due to the food choice shift of humans, and likely continue to drop because of the changing climate. These findings will guide future efforts in protecting and utilizing wheat biodiversity to improve global food security.

genetics↗

bioRxiv2022

Electron tomography analysis of the prolamellar body and its transformation into grana thylakoids in the cryofixed Arabidopsis cotyledon

The para-crystalline structure of prolamellar bodies (PLBs) and light-induced etioplasts-to-chloroplasts transformation have been investigated with electron microscopy methods. However, these studies suffer from chemical fixation artifacts and limited volumes of three-dimensional reconstruction. We have examined Arabidopsis thaliana cotyledon cells with electron tomography (ET) to visualize etioplasts and their conversion into chloroplasts. We employed the scanning mode of ET for imaging large volumes and high-pressure freezing to improve sample preservation. PLB tubules were arranged in a zinc blende-type lattice like carbon atoms in diamonds. Within 2 hours after illumination, the lattice collapsed from the PLB exterior and the disorganized tubules merged to form thylakoid sheets, a.k.a. pre-granal thylakoids. These pre-granal thylakoids in PLBs vicinity folded and overlapped with each other to create grana stacks. Since the nascent pre-granal thylakoids had curved membranes in their tips, we examined the expression and localization of CURT1 proteins. CURT1A transcript was most abundant in de-etiolating cotyledon samples, and CURT1A concentrated to the PLB periphery. In curt1a etioplasts, PLB-associated thylakoids were swollen and failed to form grana stacks. By contrast, PLBs had cracks in their lattices in curt1c etioplasts. Our data provide evidence that CURT1A is required for pre-granal thylakoid assembly from PLB tubules during de-etiolation, while CURT1C contributes to the cubic crystal growth under darkness.

plant biology↗

bioRxiv2022

Variable Selection via Grace-AKO with Applications in Genomics

MotivationVariable selection is a common statistical approach to identifying genes associated with clinical outcomes of scientific interest. There are thousands of genes in genomic studies, while only a limited number of individual samples are available. Therefore, it is important to develop a method to identify genes associated with outcomes of interest that can control finite-sample false discovery rate (FDR) in high-dimensional data settings. ResultsThis article proposes a novel method named Grace-AKO for graph-constrained estimation (Grace), which incorporates aggregation of multiple knockoffs (AKO) with the network-constrained penalty. Grace-AKO can control FDR in finite-sample settings and improve model stability simultaneously. Simulation studies show that Grace-AKO has better performance in finite-sample FDR control than the original Grace model. We apply Grace-AKO to the prostate cancer data in The Cancer Genome Atlas (TCGA) program by incorporating prostate-specific antigen (PSA) pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) as the prior information. Grace-AKO finally identifies 47 candidate genes associated with PSA level, and more than 75% of the detected genes can be validated. Availability and implementationWe developed an R package for Grace-AKO available at: https://github.com/mxxptian/GraceAKO Contactdoraz@hku.hk or zl2509@cumc.columbia.edu

bioinformatics↗

bioRxiv2022

DTSyn: a dual-transformer-based neural network to predict synergistic drug combinations

Drug combination therapies are superior to monotherapy for cancer treatment in many ways when addressing tumor heterogeneity issue. For wet-lab experiment, screening out novel synergistic drug pairs is challenging due to the enormous searching space of possible drug pairs. Thus, computational methods have been developed to predict drug pairs with potential synergistic function. Notwithstanding the success of current models, the power of generalization to other datasets as wells as understanding of mechanism for chemical-chemical interaction or chemical-sample interaction are lack of study, hindering current algorithms from real application. In this paper, we proposed a deep neural model termed DTSyn (Dual Transformer model for drug pair Synergy prediction) based on multi-head attention mechanism to identify novel drug combinations. We designed a fine-granularity transformer for capturing chemical substructure-gene and gene-gene associations and a coarse-granularity transformer for extracting chemical-chemical and chemical-cell line interactions. DTSyn achieves highest Receiver operating characteristic area under curve (ROC AUC) of 0.73, 0.78. 0.82 and 0.81 on four different cross validation tasks, outperforming all competing methods. Further, DTSyn achieved best True Positive Rate (TPR) over five independent datasets. The ablation study showed that both transformer blocks contributed to the performance of DTSyn. In addition, DTSyn can extract interactions among chemicals and cell lines, which may represent the mechanisms of drug action. Thus, we envision our model a valuable tool to prioritize synergistic drug pairs by utilizing chemicals and transcriptome data.

bioinformatics↗

bioRxiv2022

L-GIREMI uncovers RNA editing sites in long-read RNA-seq

Using third-generation sequencers, long-read RNA-seq is increasingly applied in transcriptomic studies given its major advantage in characterizing full-length transcripts. A number of methods have been developed to analyze this new type of data for transcript isoforms and their abundance. Another application, which is significantly under-explored, is to identify and analyze single nucleotide variants (SNVs) in the RNA. Identification of SNVs, such as genetic mutations or RNA editing sites, is fundamental to many biomedical questions. In long-read RNA-seq, SNV analysis presents significant challenges, due to the well-known relatively high error rates of the third-generation sequencers. Here, we present the first study to detect and analyze RNA editing sites in long-read RNA-seq. Our new method, L-GIREMI, effectively handles sequencing errors and biases in the reads, and uses a model-based approach to score RNA editing sites. Applied to PacBio long-read RNA-seq data, L-GIREMI affords a high accuracy in RNA editing identification. In addition, the unique advantage of long reads allowed us to uncover novel insights about RNA editing occurrences in single molecules and double-stranded RNA (dsRNA) structures. L-GIREMI provides a valuable means to study RNA nucleotide variants in long-read RNA-seq.

bioinformatics↗

bioRxiv2022

Genome-wide signatures of geographic expansion and breeding process in soybean

The clarification of genomic signatures left during evolutionary histories of crops is crucial for breeding varieties adapting to changing climate. Soybean, a leguminous crop, provides both plant oil and protein. Here, we analyzed genome sequences of 2,214 soybeans and proposed its evolutionary route, which includes four geographic paths, expansion of annual wild soybean (Glycine soja Sieb. & Zucc.) from Southern China, domestication in Central China, expansion of landrace (G. max (L.) Merr.), and local breeding. We observed that local adaptation of the wild and cultivated soybeans was largely independent, and that genetic introgression was mostly derived from sympatric rather than allopatric wild populations during the range expansion of soybean landraces. Range expansion and breeding processes were accompanied with positive selection of flowering-time genes including GmSPA3c as validated by knock-out mutants. Our study shed lights on the evolutionary history of soybean and provides valuable genetic resources for future breeding. TeaserThe expansion and selection history of soybean

genomics↗

bioRxiv2022

An anchored experimental design and meta-analysis approach to address batch effects in large-scale metabolomics

Large-scale untargeted metabolomics studies suffer from individual variation, batch effects and instrument variability, making comparisons of common spectral features across studies difficult. One solution is to compare studies after compound identification. However, compound identification is expensive and time consuming. We successfully identify common spectral features across multiple studies, with a generalizable experimental design approach. First, we included an anchor strain, PD1074, during sample and data collection. Second, we collected data in blocks with multiple controls. These anchors enabled us to successfully integrate three studies of Caenorhabditis elegans for nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) data from five different assays. We found 34% and 14% of features to be significant in LC-MS and NMR, respectively. Between 20-50% of spectral features differ in a mutant and among a set of genetically diverse natural strains, suggesting this reduced set of spectral features are excellent targets for compound identification. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/485859v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@84abe1org.highwire.dtl.DTLVardef@3066fforg.highwire.dtl.DTLVardef@1ba166corg.highwire.dtl.DTLVardef@164cf0_HPS_FORMAT_FIGEXP M_FIG C_FIG Fourteen C. elegans strains are used in three individual studies. PD1074, the anchor control strain (orange), is grown alongside test strains (green, yellow, purple). Multiple biological replicates of PD1074 captures environmental variation in growth conditions. Non-polar and polar metabolic data across the three studies (i.e., natural strains, central metabolism mutants, and UGT mutants) were collected by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Data acquisition controls in each block included biological reference material and pooled PD1074 samples. Biological replicates of PD1074 (n = 42 for LC-MS, n = 52 for NMR) were included in all batches. Meta-analysis provided comparable inferences to mixed effects models, and the estimated relative effects of each test strain to PD1074 and straightforward comparisons of test strains across experiments.

systems biology↗

bioRxiv2022

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology ("Stereo-seq"), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with [~]600 genes per cell for 10 m-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for [~]1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

cell biology↗

bioRxiv2022

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase response rate to checkpoint blockade, in this study we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to IL-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-Sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 led to activation of both the innate and adaptive immune response and decreased levels of transforming growth factor-{beta}1 (TGF-{beta}1) within the TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.

immunology↗

bioRxiv2022

Effect of GDF15 on acetaminophen (APAP)-induced liver injury in mice

Acetaminophen (APAP)-induced liver injury (AILI) has been recognized as a pivotal contributor to drug-induced liver failure in western countries, but its molecular mechanism remains poorly understood. After data mining using the Gene Expression Omnibus (GEO) database, we found that the gene expression of growth differentiation factor 15 (GDF15) increased significantly after APAP-induced hepatotoxicity in mouse liver. However, the precise role of GDF15 in AILI has yet to be clarified. To deal with this question, we first examined the temporal gene expression pattern of GDF15 after APAP treatment. Next, overexpression of hepatic GDF15 using adeno-associated virus serotype 8 (AAV8) was employed to investigate the role of GDF15 in AILI. In addition, therapeutic administration of recombinant human GDF15 (rhGDF15) was conducted to probe its curative effect after APAP overdose. We observed that protein expression of GDF15 was significantly increased after APAP overdose. However, there were no significant differences in AILI-related outcomes after overexpression or supplementation of GDF15. The contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), morphological feature of liver, the level of reduced form of glutathione (GSH), the activation of c-Jun-N-terminal kinase (JNK), the expression of genes relevant to oxidative stress and cell proliferation were not remarkably changed between AAV8-GFP and AAV8-Gdf15 groups. Although the liver injury was not improved by rhGDF15 administration, the gene expression levels of glutamate-cysteine ligase modifier subunit (Gclm) and glutamate-cysteine ligase catalytic subunit (Gclc) which function downstream of Nrf2 signaling pathway were significantly increased. Altogether, despite a noticeable elevated expression after APAP overdose, GDF15 overexpression or supplementation exerted no significant ameliorative effect on AILI. Further mechanism and consequence of Gclm and Gclc elevation by GDF15 remains to be elucidated.

pharmacology and toxicology↗

bioRxiv2022

A global pangenome for the wheat fungal pathogen Pyrenophora tritici-repentis and prediction of effector protein structural homology

The adaptive potential of plant fungal pathogens is largely governed by the gene content of a species, comprised of core and ancillary genes across the pathogen isolate repertoire. To approximate the complete gene repertoire of a globally significant crop fungal pathogen, a pan genomic analysis was undertaken for Pyrenophora tritici-repentis (Ptr), the causal agent of tan (or yellow) spot disease in wheat. In this study, fifteen new Ptr genomes were sequenced, assembled and annotated, including isolates from three races not previously sequenced. Together with eleven previously published Ptr genomes, a pangenome for twenty-six Ptr isolates from Australia, Europe, North Africa and America, representing nearly all known races, revealed a conserved core-gene content of 57% and presents a new Ptr resource for searching natural homologues using remote protein structural homology. Here, we identify for the first time a nonsynonymous mutation in the Ptr effector gene ToxB, multiple copies of toxb, a distant natural Pyrenophora homologue of a known Parastagonopora nodorum effector, and clear genomic break points for the ToxA effector horizontal transfer region. This comprehensive genomic analysis of Ptr races includes nine isolates sequenced via long read technologies. Accordingly, these resources provide a more complete representation of the species, and serve as a resource to monitor variations potentially involved in pathogenicity. Author NotesAll supporting data, code and protocols have been provided within the article or through supplementary data files. Five supplementary data files and fifteen supplementary figures are available with the online version of this article. Impact StatementOur Pyrenophora tritici-repentis (Ptr) pangenome study provides resources and analyses for the identification of pathogen virulence factors, of high importance to microbial research. Key findings include: 1) Analysis of eleven new sequenced (with three new races not previously available) and previously published isolates, 26 genomes in total, representing the near complete Ptr race set for known effector production collected from Australia, Europe, North Africa and the Americas. 2) We show that although Ptr has low core gene conservation, the whole genome divergence of other wheat pathogens was greater. 3) The new PacBio sequenced genomes provide unambiguous genomic break points for the large ToxA effector horizontal transfer region, which is only present in ToxA producing races. 4) A new web-based Ptr resource for searching in silico remote protein structural homology is presented, and a distant natural Pyrenophora protein homologue of a known effector from another wheat pathogen is identified for the first time. Data SummaryThe sources and genomic sequences used throughout this study have been deposited in the National Centre for Biotechnology Information (NCBI), under the assembly accession numbers provided in Tables 1 and 2 (available in the online version of this article). The new M4 resource for protein structural homology is freely available through the BackPhyre web-portal URL, http://www.sbg.bio.ic.ac.uk/phyre2/. O_TBL View this table: org.highwire.dtl.DTLVardef@c6b2deorg.highwire.dtl.DTLVardef@1091da1org.highwire.dtl.DTLVardef@17860a4org.highwire.dtl.DTLVardef@10d4aaorg.highwire.dtl.DTLVardef@fa258f_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1.C_FLOATNO O_TABLECAPTIONSummary statistics for our four PacBio sequenced Ptr genome assemblies, compared with those of two previously published Ptr assemblies. C_TABLECAPTION C_TBL O_TBL View this table: org.highwire.dtl.DTLVardef@b7d0cforg.highwire.dtl.DTLVardef@1ee01e6org.highwire.dtl.DTLVardef@becc09org.highwire.dtl.DTLVardef@456c7corg.highwire.dtl.DTLVardef@1d55799_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 2.C_FLOATNO O_TABLECAPTIONIllumina sequenced genome assemblies of 11 new Ptr isolates. Table shows isolate source, race and de novo assembly statistics. C_TABLECAPTION C_TBL

genomics↗

bioRxiv2022

Single-cell RNA Sequencing of Pediatric Ependymoma Unravels Subclonal Heterogeneity Associated with Patient Survival

Ependymoma (EPN) is a malignant glial tumor occurring throughout central nervous system which commonly presents in children. Although recent studies have characterized EPN samples at both the bulk and single-cell level, intra-tumoral heterogeneity across subclones remains a confounding factor which impedes understanding of EPN biology. In this study, we generated a high-resolution single-cell dataset of pediatric ependymoma with a particular focus on the comparison of subclone differences within tumors, and show upregulation of cilium-associated genes in more highly differentiated subclone populations. As a proxy to traditional pseudotime analysis, we applied a novel trajectory scoring method to reveal cellular compositions associated with poor survival outcomes across primary and relapsed patients. Furthermore, we identified putative cell-cell communication features between relapsed and primary samples and show upregulation of pathways associated with immune cell crosstalk. Our results reveal both inter- and intratumoral gene expression profiles and tumor differentiation and provide a framework for studying transcriptomic signatures of individual subclones in ependymoma at single-cell resolution.

bioinformatics↗

bioRxiv2022

DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Confers Chemoresistance via Activation of YAP Signaling

Squamous cell carcinomas (SCCs) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel chemosensitizer targets, we performed whole-transcriptome sequencing of paired resistant/parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 associates with histones to regulate the distal elements of FAM3 metabolism regulating signaling molecule D (FAM3D) and reduces extracellular FAM3D protein secretion. FAM3D interacts with Gi-coupled G protein-coupled receptor (GPCR) formyl peptide receptor (FPR) 1 and FPR2 to suppress phospholipase D (PLD) activity; thus, reduced FAM3D activates PLD signaling. Moreover, activated PLD promotes phosphatidic acid (PA) production and subsequent yes-associated protein (YAP) nuclear translocation. Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitizes SCC to cisplatin treatment. In summary, our study reveals that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential in SCC chemoresistance and that D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents. SignificanceThis study identifies D-AS2 as a targetable lipid-related lncRNA that activates YAP signaling via PLD/PA axis to trigger chemoresistance in SCC.

cancer biology↗

bioRxiv2022

Genome-wide Association Study Reveals that PvGUX1_1 is Associated with Pod Stringlessness in Snap Bean (Phaseolus vulgaris L.)

The suture strings is a particularly important pod trait that determines the quality and texture of snap bean (Phaseolus vulgaris L.). The St locus on chromosome 2 has been described as a major locus associated with suture strings. However, the gene and genetic basis underlying this locus remain unknown. Here, we investigated the suture strings of 138 snap bean accessions across two years. A total of 3.66 million single-nucleotide polymorphisms (SNPs) were obtained by deep resequencing. Based on these SNPs, we identified a strong association signal on Chr02 and a promising candidate gene, PvGUX1_1. Further analysis revealed that the 2-bp deletion in exon of PvGUX1_1 was significantly associated with stringlessness. Comparative mapping indicated that PvGUX1_1 was a domesticated locus and diverged from PvGUX1_2 during an early stage. Our study provides important insights into the genetic mechanism of suture string formation and useful information for snap bean improvement.

genetics↗