Biology subjects

Xu, W.

Publications and source records attributed to Xu, W..

At least 325 records · Page 18Linked to original sources

bioRxiv2019

Genome and community-level interaction insights on wide carbon utilizing and element cycling function of Hydrothermarchaeota from hydrothermal sediment

Hydrothermal vents release reduced compounds and small organic carbons into surrounding seawaters, providing essential substrates for microbial-derived biosynthesis and bioenergy transformations. Despite the wide distribution of Marine Benthic Group-E archaea (referred to as Hydrothermarchaeota) in hydrothermal environments, little is known on their genome blueprints and ecofunctions. Here, we studied four relatively high-completeness (> 80%) metagenome-assembled genomes (MAGs) from a black smoker chimney and surrounding sulfide sediments in the Mid-Atlantic Ridge of the South Atlantic Ocean (BSmoChi-MAR) as well as publicly available datasets. Comparative genomics suggest that Hydrothermarchaeota members have versatile carbon metabolism, including assimilating proteins, lactate and acetate, degrading aromatics anaerobically, oxidizing C1 compounds (CO, formate, and formaldehyde), utilizing methyl-compounds, and incorporating CO2 by tetrahydromethanopterin-based Wood-Ljungdahl (WL) pathway and Calvin-Benson-Bassham (CBB) cycle with type III Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO). They could oxidize sulfur, arsenic, and hydrogen, and respire anaerobically via sulfate reduction and denitrification based on genomic evidence. The redundancy of carbon utilizing and element cycling functions, and the interactive processes of syntrophic and sequential utilization of substrates from community-level metabolic prediction, enable wide accessibility of carbon and energy sources to microorganisms. Hydrothermarchaeota members derived important functional components from the community through lateral gene transfer, and became clade-distinctive on genome content, which might serve as a niche-adaptive strategy to metabolize potential heavy metals, C1 compounds, and reduced sulfur compounds.\n\nImportanceThis study provides comprehensive metabolic insights on Hydrothermarchaeota from comparative genomics, evolution and community-level aspects. Hydrothermarchaeota synergistically participates in a wide range of carbon utilizing and element cycling processes with other microbes in the community. We expand the current understanding of community interactions within hydrothermal sediment environments, suggesting that microbial interactions driven by functions are essential to nutrient and element cycling.

ecology↗

bioRxiv2019

DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis

BackgroundIt is becoming increasingly important to understand the mechanism of regulatory elements on target genes in long-range genomic distance. 3C (Chromosome Conformation Capture) and its derived methods are now widely applied to investigate genome organizations and gene regulation. Digestion-Ligation-Only Hi-C (DLO Hi-C) is a new technology with high efficiency and effective cost for whole-genome chromosome conformation capture.\n\nResultsHere, we introduce DLO Hi-C Tool, a flexible and versatile pipeline for processing DLO Hi-C data from raw sequencing reads to normalized contact maps and providing quality controls for different steps. It includes more efficient iterative mapping and linker filtering. We applied DLO Hi-C Tool to different DLO Hi-C datasets, and demonstrated its ability of processing large data in multi-threading.\n\nConclusionsDLO Hi-C Tool is suitable for processing DLO Hi-C and in situ DLO Hi-C datasets. It is convenient and efficient for DLO Hi-C data processing.

bioinformatics↗

bioRxiv2019

Epitope containing short peptides capture distinct IgG serodynamics that enable DIVA for live-attenuated vaccines

Differentiating infected from vaccinated animals (DIVA) strategies have been central enabling techniques in several successful viral disease elimination programs. However, owing to their long and uncertain development process, no DIVA-compatible vaccines are available for many important diseases. We report herein a new DIVA strategy based on hybrid protein-peptide microarrays which can theoretically work with any vaccine. Leading from our findings from Peste des petits ruminants (PPR), we found 4 epitope containing short peptides (ECSPs) which have distinct IgG serodynamics: anti-ECSP IgGs only exist for 10-60 days post vaccination (dpv), while anti-protein IgGs remained at high levels for >1000 dpv. These data enabled design of a DIVA diagnostic microarray containing 4 ECSPs and 3 proteins, which unlike cELISA and VNT, enables ongoing monitoring of serological differences between vaccinated individuals and individuals exposed to the pathogen. For 50 samples after 60 dpv, 20 animals were detected with positive anti-ECSP IgGs, indicating recent infections in vaccinated goat/sheep herds. These DIVA diagnostic microarrays will almost certainly facilitate eradication programs for (re-)emerging pathogens and zoonoses.

immunology↗

bioRxiv2019

Robust Hi-C chromatin loop maps in human neurogenesis and brain tissues at high-resolution

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input \"easy Hi-C\" (eHi-C) protocol to map the 3D genome architecture in neurogenesis and brain tissues, and also developed an improved Hi-C bias-correction pipeline (HiCorr) enabling better identification of enhancer loops or aggregates at sub-TAD level. We compared ultra-deep 3D genome maps from 10 human tissue- or cell types, with a focus on stem cells and neural development. We found several large loci in skin-derived human iPSC lines showing recurrent 3D compartmental memory of somatic heterochromatin. Chromatin loop interactions, but not genome compartments, are hallmarks of neural differentiation. Interestingly, we observed many cell type- or differentiation-specific enhancer aggregates spanning large neighborhoods, supporting a phase-separation mechanism that stabilizes enhancer contacts during development. Finally, we demonstrated that chromatin loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.\n\nHighlightsO_LILow input \"easy Hi-C\" protocol compatible with 50-100K cells\nC_LIO_LIImproved Hi-C bias correction allows direct observation and accurate identification of sub-TAD chromatin loops and enhancer aggregates\nC_LIO_LIRecurrent architectural memory of somatic heterochromatin at compartment level in skin-derived hiPSCs\nC_LIO_LIChromatin loop, but not genome compartment, marks neural differentiation\nC_LIO_LIChromatin loop outperforms eQTL in defining brain GWAS target genes\nC_LI

genomics↗

bioRxiv2019

N-Acetyl Cysteine Alleviates Coxsackievirus B-Induced Myocarditis by Suppressing caspase-1

Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective medicine is available to treat CVB infection. Here we evaluated the anti-CVB effect of N-acetyl cysteine (NAC), a widely used antioxidant. NAC significantly alleviated myocarditis and improved the overall condition of CVB type 3 (CVB3)-infected mice. Importantly, NAC treatment suppressed viral replication in both myocardium and cell culture. We show that NAC inhibited CVB3 replication when it was applied at the early stage of CVB3 infection. NACs antiviral mechanism, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation, since the knockdown of caspase-1 blocked CVB3 replication. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which may further contribute to the inhibited activity of caspase-1. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB effect by inhibiting caspase-1 and viral proteases. This study suggests that NAC can be a safe therapeutic option for CVB-induced myocarditis.

microbiology↗

bioRxiv2019

Allicin regulates energy homeostasis through brown adipose tissue

Background/objectivesDisorder of energy homeostasis can lead to a variety of metabolic diseases, especially obesity. Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a main bioactive ingredient in garlic, has multiple biology and pharmacological function. However, the role of Allicin, in the regulation of metabolic organ, especially the role of activation of BAT, has not been well studied. Here, we analyzed the role of Allicin in whole-body metabolism and the activation of BAT.\n\nResultsAllicin had a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in diet-introduced obesity (DIO) mice. Then we find that Allicin can strongly activate brown adipose tissue (BAT). The activation of brown adipocyte treated with Allicin was also confirmed in mouse primary brown adipocytes.\n\nConclusionAllicin can ameliorate obesity through activating brown adipose tissue. Our findings provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

molecular biology↗

bioRxiv2019

Drug target discovery via network modeling: a mathematical model of the E. coli folate network response to trimethoprim

The antibiotic trimethoprim targets the bacterial dihydrofolate reductase enzyme and subsequently affects the entire folate network. We present an expanded mathematical model of trimethoprims action on the Escherichia coli folate network that greatly improves upon Kwon et al. (2008). The improvement upon the Kwon Model lends greater insight into the effects of trimethoprim at higher resolution and accuracy. More importantly, the presented mathematical model enables drug target discovery in a way the earlier model could not. Using the improved mathematical model as a scaffold, we use parameter optimization to search for new drug targets that replicate the effect of trimethoprim. We present the model and model-scaffold strategy as an efficient route for drug target discovery.

systems biology↗

bioRxiv2019

Oncoprotein CoAA repeats interact with RNA polymerase II CTD repeats

The heptad repeating sequence of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II is highly conserved in eukaryotes. In yeast, a CTD code consisting of pairs of heptad repeats is essential for viability. However, the strict requirement of diheptad repeats for the CTD function in transcription and splicing is unexplained. Here we show that CoAA (gene symbol RBM14), an oncoprotein and mammalian transcriptional coactivator, possesses diheptad repeats and directly interacts with the CTD. CoAA comprises 27 copies of tyrosine-rich repeats and regulates pre-mRNA synthesis and alternative splicing. Tyrosine substitutions in either the CoAA repeats or the CTD repeats diminish their interactions. Ser2- or Ser5-phosphorylated CTD peptides exhibit higher binding affinity to CoAA than the corresponding non-phosphorylated CTD peptide. CoAA dynamically interacts with both the CTD and hnRNP M, which is an alternative splicing regulator also comprising diheptad repeats. Arginine methylation of CoAA switches its interaction from the hnRNP M repeats to the CTD repeats. This study provides a mechanism for CoAA at the interface of transcription and alternative splicing, and explains the functional requirement of diheptad repeats in the CTD. In the human genome, tyrosine-rich repeats similar to the CoAA repeats were only found in six oncoproteins including EWS and SYT. We suggest that the diheptad sequence is one of the signature features for the CTD interaction among oncoproteins involved in transcription and alternative splicing. We anticipate that direct RNA Pol II interaction is a mechanism in oncogenesis.

biochemistry↗

bioRxiv2019

Targeting glutamine metabolism enhances tumor specific immunity by inhibiting the generation of MDSCs and reprogramming tumor associated macrophages

Myeloid cells comprise a major component of the Tumor Microenvironment (TME) promoting tumor growth and immune evasion. By employing a novel small molecule inhibitor of glutamine metabolism not only were we able to inhibit tumor growth but we markedly inhibited the generation and recruitment of Myeloid Derived Suppressor Cells (MDSC). Targeting tumor glutamine metabolism led to a decrease in CSF-3 and hence recruitment of MDSC as well immunogenic cell death leading to an increase in inflammatory Tumor Associated Macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSC themselves led to activation induced cell death and conversion of MDSC to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid derived cells leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced anti-tumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.

immunology↗

bioRxiv2019

Base editing in Streptomyces with Cas9-deaminase fusions

Conventional CRISPR/Cas genetic manipulation has been profitably applied to the genus Streptomyces, the most prolific bacterial producers of antibiotics. However, its reliance on DNA double-strand break (DSB) formation leads to unacceptably low yields of desired recombinants. We have adapted for Streptomyces recently-introduced cytidine base editors (CBEs) and adenine base editors (ABEs) which enable targeted C-to-T or A-to-G nucleotide substitutions, respectively, bypassing DSB and the need for a repair template. We report successful genome editing in Streptomyces at frequencies of around 50% using defective Cas9-guided base editors and up to 100% by using nicked Cas9-guided base editors. Furthermore, we demonstrate the multiplex genome editing potential of the nicked Cas9-guided base editor BE3 by programmed mutation of nine target genes simultaneously. Use of the high-fidelity version of BE3 (HF-BE3) essentially improved editing specificity. Collectively, this work provides a powerful new tool for genome editing in Streptomyces.

microbiology↗

bioRxiv2019

CoolBox: a interactive genomic data explorer for Jupyter Notebook

SummaryCoolBox is a Python package for interactive genomic data exploration based on Jupyter notebook. It provides a ggplot2-like Application Programming Interface (API) for genomic data visualization, and a Jupyter/ipywidgets based Graphical User Interface (GUI) for interactive data exploration. CoolBox is a versatile multi-omics explorer supporting most types of data formats generated by various sequencing technologies like RNA-Seq, ChIP-Seq, ChIA-PET and Hi-C.\n\nAvailability and implementationCoolBox is purely implemented with Python, and the GUI widget in Jupyter notebook is based on the ipywidgets package. It is open-source and available under GPLv3 license at https://github.com/GangCaoLab/CoolBox.

bioinformatics↗

bioRxiv2019

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit results in the creation of two genes

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene fixed in two laboratory strains of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.B and NURF-1.D, which we call Yin and Yang) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional biproducts necessary to transcribe the Yin and Yang transcripts in the same cells. Our work suggests that evolution of nurf-1 isoforms in nematodes creates adaptive conflict that can be resolved by the creation of new, independent genes.

evolutionary biology↗

bioRxiv2019

Intronic heterochromatin prevents cryptic transcription initiation in Arabidopsis

Intronic transposable elements (TEs) comprise a large proportion in eukaryotic genomes, but how they regulate the host genes remains to be explored. Our forward genetic screen disclosed the plant specific RNA polymerases IV and V in suppressing intronic TE-mediated cryptic transcription initiation of a chimeric transcripts at FLC (FLCTE). Initiation of FLCTE transcription is blocked by the locally formed intronic heterochromatin, which is directly associated with RNA Pol V to inhibit the entry of RNA Pol II and the occupancy of H3K4 methylation. Genome-wide Pol II Ser5p native elongation transcription sequencing revealed that this is a common mechanism among intronic heterochromatin-containing genes. This study sheds light on deeply understanding the function of intronic heterochromatin on host genes expression in eukaryotic genome.

plant biology↗

bioRxiv2019

Dental calculus as a tool to study the evolution of the oral microbiome in mammals

Animals and their associated microbiomes share a long evolutionary history, influenced by a complex interplay between extrinsic environmental and intrinsic host factors. However, we know little about microbiome responses to long-lasting environmental and host-centred processes, which require studying microbiome changes through time. Here, we apply a temporal metagenomics approach to dental calculus, the calcified oral microbial biofilm. We establish dental calculus as a valuable tool for the study of host microbiome evolution by characterising the taxonomic and functional composition of the oral microbiome in a variety of wild mammals. We detect oral pathogens in individuals with evidence of oral disease, assemble near-complete bacterial genomes from historical specimens, characterise antibiotic resistance genes even before the advent of industrial antibiotic production, reconstruct components of the host diet and recover host genetic profiles. Our work demonstrates how dental calculus can be used in the future to study the evolution of oral microbiomes and pathogens, and the impact of anthropogenic changes on wildlife and the environment.

evolutionary biology↗

bioRxiv2019

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73-associated reduction of invasiveness act via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

biochemistry↗

bioRxiv2019

IMCC: Quantitative Analysis of the Inter-module Connectivity for Bio-network

Inter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation. A quantitative evaluation method for inter-module connections is needed. Here, based on the high-throughput microarray data from mouse, an evaluation approach (named as IMCC) for inter-module connectivity was developed. The IMCC model, which is an integration of direct and indirect inter-module connections, successfully excluded inter-module connections without statistical significance or below the cutoff value, and provided a more comprehensive landscape of inter-module relationships. We showed that the IMCC method reflected a more precise functional coordination between modules according to KEGG database, were validated by topological parameter. Application of IMCC in genome-scale stroke networks deciphered characteristic pathological \"core-periphery\" structure of modular map and functional coordination module pair.\n\nAuthor summeryInter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Moreover, modular rearrangements provide more efficient ways for phenotype alteration, inter-module connections have been considered to be evolutionary interaction switches\". Such modular map rewiring can be used as a network biomarker to characterize the dynamics of drug responses. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation response to disease or drug. We aim to construct a quantitative evaluation method for inter-module connections. Thus, this study has implications in systematical exploration detailed variation of inter-module pharmacological action mode of drugs.

systems biology↗

bioRxiv2018

The rice G protein γ subunit qPE9-1 positively regulates grain-filling process by interacting with abscisic acid and auxin

The rice genome contains a single G (RGA1) and G{beta} (RGB1) and five G{gamma} subunits. Recent genetic studies have shown that DEP1/qPE9-1, an atypical putative G{gamma} protein, is responsible for dense and erect panicles, but the biochemical and molecular mechanisms underlying control of grain size are not well understood. Here, we report that plants carrying qPE9-1 have more endosperm cells per grain than plants contain the qpe9-1 allele. The qPE9-1 line has a higher rate and longer period of starch accumulation than the qpe9-1 line. Additionally, the expression of several key genes encoding enzymes catalyzing sucrose metabolism and starch biosynthesis is higher in the qPE9-1 line than in the qpe9-1 line, especially from the mid to late grain-filling stage. Grains of the qPE9-1 line also have higher contents of two phytohormones, ABA and IAA. Exogenous application of ABA or IAA enhanced starch accumulation and the expression of genes encoding grain-filling-related enzymes in the grains of qPE9-1, whereas only IAA produced these effects in qpe9-1. Based on these results, we conclude that qPE9-1 promotes endosperm cell proliferation and positively regulates starch accumulation largely through ABA and IAA, which enhance the expression of genes encoding starch biosynthesis during the late grain-filling stage.

plant biology↗

bioRxiv2018

Enrichment of short mutant cell-free DNA fragments enhanced detection of pancreatic cancer

Analysis of cell-free DNA (cfDNA) is promising for broad applications in clinical settings, but with significant bias towards late-stage cancers. Although recent studies have discussed the diverse and degraded nature of cfDNA molecules, little is known about its impact on the practice of cfDNA analysis. Here we reported a new targeted sequencing by combining single-strand library preparation and target capture (SLHC-seq). By applying the new technology in plasma cfDNA from pancreatic cancer patients, we achieved higher efficiency in analysis of mutations than previously reported using other detection assays. SLHC-seq rescued short or damaged cfDNA fragments along to increase the sensitivity and accuracy of circulating-tumor DNA detection. Most importantly, we found that the small mutant fragments are prevalent in early-stage patients, which provides strong evidence for fragment size-based early detection of pancreatic cancer. Collectively, the new pipeline enhanced our understanding of cfDNA biology and provide new insights for liquid biopsy.

cancer biology↗