Biology subjects

Jia, W.

Publications and source records attributed to Jia, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

DAB2IP inhibits p53 ubiquitin-mediated degradation by competitively binding to GRP75 and suppresses tumor malignancy in colon cancer

Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibition role in many tumors. However, the underlying mechanism is still uncertain. Our study shows that DAB2IP is positively associated with a better prognosis in colon cancer patients with wild-type TP53 expression. In vitro assay shows that DAB2IP elicits potent tumor-suppressive effects on inhibiting cell invasiveness, colony formation and promoting cell apoptosis in wild-type TP53 colon cancer cell lines. Subsequently, DAB2IP is demonstrated to up-regulate the stability of wild-type TP53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we unveil that DAB2IP and p53 could both interact with the ubiquitin ligase-related protein, GRP75. Mechanistically, DAB2IP could competitively bind with GRP75, thus reducing GRP75-mediated p53 ubiquitination and degradation. Finally, animal experiments also reveal that DAB2IP inhibits the tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, which provides a new insight in DAB2IP-induced tumor suppression and provides a novel molecular aspect of the p53 pathway.

cancer biology↗

bioRxiv2021

CNAHap: a germline haplotyping method using tumor allele-specific copy number alteration

Haplotype phasing is indispensable to study human genetics. The pervasiveness of large copy number variant segments in solid tumors brings possibilities to resolve long germline phasing blocks utilizing allele imbalance in tumor data. Although there exist such studies, none of them provide easy-use software based on availability and usability. Herein, we present a novel tool, CNAHap, to determine the allele-specific copy number in tumor and then phase germline variants according to the imbalanced alleles in tumor genomes. We also provide interactive web interfaces to visualize the copy number and phase landscape from CNAHap. On in silico datasets, CNAHap demonstrates higher allele-specific copy number calling accuracy than the benchmark tool and generates long phasing blocks. As a case study on Hepatocellular carcinoma, CNAHap successfully generates huge phase blocks with the averages of N50 and N90 as 25M and 7M, respectively, and finds the Olfactory receptor family is recurrent amplified. Our results illustrate the efficacy of CNAHap in determining tumor allele-specific copy numbers and their long germline haplotypes. CNAHap is available at https://github.com/bowentan/CNAHap and the CNAHap visualization web interfaces are hosted at bio.oviz.org.

bioinformatics↗

bioRxiv2021

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through its enhancer in breast cancer

Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the mechanism remains to be elucidated. Here, we reported that YAP1 could induce invadopodia formation and promote tumor metastasis in breast cancer cells. We identified that TIAM1, the guanine nucleotide exchange factor, is a target of YAP1-TEAD4 complex. YAP1 promotes TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression and subsequently increases RAC1 activity. These findings reveal the functional role of Hippo signaling in invadopodia, and provide potential molecular targets for preventing tumor metastasis in breast cancer. SignificanceThrough regulating the enhancer region of TIAM1, YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer.

cancer biology↗

bioRxiv2020

Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis

Background and purposeSodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. However, the toxic effect of SB remains largely unknown. This issue is addressed in current study. Experimental approachSB (0.3 - 2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brain hypothalamus were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. Key resultsThe temperature was reduced by SB (1.2 -2.5 g/kg) in a dose-dependent manner in mice for 2-4 hr. In the brain, the effect was associated with SB elevation and neurotransmitter (Glutamate and GABA) reduction. The mitochondria exhibited a transient volume expansion and crista loss in the hypothalamic neurons. ADP/ATP ratio was increased with accumulation of intermediate metabolites in the glycolysis, TCA cycle and pentose phosphate pathways. The mitochondrial protein, adenine nucleotide transporter (ANT), was activated for proton transportation leading to a transient potential collapse by proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. The temperature drop was attenuated by i.p. injection of norepinephrine. The HDAC inhibitors, such as SAHA and pyruvate, did not exhibit the same effect. Conclusion and implicationsSuper-dosed SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial reprogramming in the brain. The mechanism was quick activation of ANT proteins for the proton leak in mitochondria.

pharmacology and toxicology↗

bioRxiv2020

Single-cell immune landscape of human recurrent spontaneous abortion

Successful pregnancy in placental mammals substantially depends on the establishment of maternal immune tolerance to the semi-allogenic fetus. Disorders in this process are tightly associated with adverse pregnancy outcomes including recurrent spontaneous abortion (RSA). However, an in-depth understanding of the disorders from the aspect of systematic and decidual immune environment in RSA remains largely lacking. In this study, we utilized single-cell RNA-sequencing to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and RSA pregnancies at the early stage of gestation. Integrative analysis identified 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RSA cases was revealed. Specifically, the cytotoxic properties of CD8T effector, NK, and MAIT cells in peripheral blood indicated apparently enhanced immune inflammatory status, and the subpopulation proportions and ligand-receptor interactions of the decidual leukocyte subsets demonstrated preferential immune activation in RSA patients. The molecular features, spatial distribution and the developmental trajectories of five decidual NK (dNK) subsets were illustrated. The proportion of a dNK subset responsible for fetal protection was reduced, while the ratio of another dNK subset with cytotoxic and immune-active signature was significantly increased. Notably, a unique pro-inflammatory CD56+CD16+ dNK subpopulation was substantially accumulated in RSA decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy, which provides an in-depth insight into the immune pathogenesis for early pregnancy loss.

immunology↗

bioRxiv2020

Caloric Restriction Remodels Energy Metabolic Pathways of Gut Microbiota and Promotes Host Autophagy

Calorie restriction (CR) can improve the metabolic balance of adults and elevate the relative abundance of probiotic bacteria in the gut while promoting longevity. However, the interaction between remodeled intestinal flora and metabolic improvement, as well as the mechanism for probiotic bacterial increase, are still unclear. In this study, using a metabolomics platform, we demonstrate for the first time, that CR leads to increased levels of malate and its related metabolites in biological samples. Next, we investigated the effects of CR on the gut microbial genome and the expression of mRNA related to energy metabolism which revealed a partially elevated TCA cycle and a subsequently promoted glyoxylate cycle, from which large amounts of malate can be produced to further impact malate related pathways in the host liver. Through the identification of key "hungry" metabolites produced by the gut microbiota that function in the promotion of autophagy in the host, further insight has been gained about a functional metabolic network important for both host-microbial symbiosis and maintenance of host health.

systems biology↗

bioRxiv2020

Conjugate graph resolves the complex structures at the virus integration loci with NGS data

Oncovirus integrations cause copy number variations (CNVs) and complex structural variations (SVs) on host genomes. However, the understanding of how inserted viral DNA impacts the local genome remains limited. The linear structure of the oncovirus integrated local genomic map (LGM) will lay the foundations to understand how oncovirus integrations emerge and compromise the host genome s functioning. We propose a conjugate graph model to reconstruct the rearranged local genomic map at integrated loci. Simulation tests prove the reliability and credibility of the algorithm. Applications of the algorithm to whole-genome sequencing data of Human papillomavirus (HPV) and hepatitis B virus (HBV)-infected cancer samples gained biological insights on oncovirus integrations. We observed five affection patterns of oncovirus integrations from the HPV and HBV-integrated cancer samples, including the exon loss, promoter gain, hyper-amplification of tumor gene, the viral cis-regulation inserted at the single intron and at the intergenic region. We found that the focal duplicates and host SVs are frequent in the HPV-integrated LGMs, while the focal deletions and complex virus SVs are prevalent in HBV-integrated LGMs. Furthermore, with the results yields from our method, we found the enhanced microhomology-mediated end joining (MMEJ) might lead to both HPV and HBV integrations, and conjectured that the HPV integrations might mainly occur during the DNA replication process. The conjugate graph algorithm code and LGM construction pipeline, available at https://github.com/deepomicslab/FuseSV. Key pointsO_LIConjugate graph model resolves complex local genomic strcuture at oncovirus integration loci. C_LIO_LILocal genome maps reveal five affection patterns of oncovirus integrations. C_LIO_LIMicrohomology bases and small insertions are enriched at the junctions of structural variations and virus integrations. C_LIO_LIHPV and HBV integrations may be induced by the enhanced microhomology-meditated mechanism. C_LI

bioinformatics↗

bioRxiv2020

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

cancer biology↗

bioRxiv2020

Fused in sarcoma regulates DNA replication timing and progression

Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction with FUS-/- cells to ascertain roles of FUS in genome protection. FUS-/- cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.

genomics↗

bioRxiv2020

CovProfile: profiling the viral genome and gene expressions of SARS-COV2

The SARS-CoV-2 virus has infected more than one million people worldwide to date. Knowing its genome and gene expressions is essential to understand the virus mechanism. Here, we propose a computational tool CovProfile to detect the viral genomic variations as well as viral gene expressions from the sequences obtained from Nanopore devices. We applied CovProfile to 11 samples, each from a terminally ill patient, and discovered that all the patients are infected by multiple viral strains, which might affect the reliability of phylogenetic analysis. Moreover, the expression of viral genes ORF1ab gene, S gene, M gene, and N gene are high among most of the samples. While performing the tests, we noticed a consistent abundance of transcript segments of MUC5B, presumably from the host, across all the samples.

bioinformatics↗

bioRxiv2020

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional. Suppl Figures: https://doi.org/10.6084/m9.figshare.11794059.v5

physiology↗

bioRxiv2020

Genome architecture and transcription data reveal allelic bias during the cell cycle

Every human somatic cell inherits a maternal and a paternal genome, which work together to give rise to cellular phenotypes. However, the allele-specific relationship between gene expression and genome structure through the cell cycle is largely unknown. By integrating haplotype-resolved genome-wide chromosome conformation capture, mature and nascent mRNA, and protein binding data, we investigate this relationship both globally and locally. We introduce the maternal and paternal 4D Nucleome, enabling detailed analysis of the mechanisms and dynamics of genome structure and gene function for diploid organisms. Our analyses find significant coordination between allelic expression biases and local genome conformation, and notably absent expression bias in universally essential cell cycle and glycolysis genes. We propose a model in which coordinated biallelic expression reflects prioritized preservation of essential gene sets.

bioinformatics↗

bioRxiv2019

SpecHap: a fast haplotyping method based on spectral graph theory

Haplotype phasing is essential to study diploid eukaryotic organisms. High-throughput sequencing, including next-generation sequencing and third-generation sequencing from different technologies, brings possibilities for haplotype assembly. Although there exist multiple haplotype phasing algorithms, only a few are portable across sequencing technologies with the premise of efficiency and accuracy. Herein, we proposed SpecHap, a novel haplotype assembly tool that leverages spectral graph theory, transforming haplotype phasing into an algebraic problem. On both in silico and whole-genome-sequencing datasets, SpecHap consumed less memory and required less CPU time, yet achieved comparable accuracy comparing to state-of-art methods across all the test instances of next-generation sequencing, linked-reads, high-throughput chromosome conformation capture sequencing, PacBio single-molecule real-time sequencing and Oxford Nanopore long-reads sequencing data. Furthermore, SpecHap successfully phased an individual Ambystoma mexicanumm, a species with gigantic diploid genomes, within 6 CPU hours and 945MB peak memory usage, while other tools failed to yield results either due to a memory overflow (40GB) or a time limit excess (5 days). Our results demonstrated that SpecHap is scalable, efficient and accurate for diploid phasing, supporting diverse sequencing platforms.

bioinformatics↗

bioRxiv2019

LandScape: a web application for interactive genomic summary visualization

SummaryVisualizing integrated-level data from genomic research remains a challenge, as it requires sufficient coding skills and experience. Here, we present LandScapeoviz, a web-based application for interactive and real-time visualization of summarized genetic information. LandScape utilizes a well-designed file format that is capable of handling various data types, and offers a series of built-in functions to customize the appearance, explore results, and export high-quality diagrams that are available for publication. Availability and implementationLandScape is deployed at bio.oviz.org/demo-project/analyses/landscape for online use. Documentation and demo data are freely available on this website and GitHub (github.com/Nobel-Justin/Oviz-Bio-demo). Contactshuaicli@cityu.edu.hk

bioinformatics↗

bioRxiv2019

Peripheral Serum Metabolomic Profiles InformAntecedent Central Cognitive Impairment in Older Adults

The incidence of Alzheimers disease (AD) increases with age and is a significant cause of worldwide morbidity and mortality. However, the metabolic perturbations behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of six metabolites, GLCA, petroselinic acid, linoleic acid, myristic acid, palmitic acid, and palmitoleic acid as well as the DCA/CA ratio, along with the dysregulation scores of three metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences in diagnostic groups across both brain and serum (P-value < 0.05).Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median of AUC = 0.772 for the metabolite level model; median of AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials. Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.

neuroscience↗

bioRxiv2019

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Alzheimers disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.

systems biology↗

bioRxiv2019

Variations of gut microbiome profile under different storage conditions and preservation periods: A multi-dimensional evaluation

Gut dysbiosis contributes to the development of various human diseases. There are thousands of publications per year for investigating the role of gut microbiota in development of various diseases. However, emerging evidence has indicated data inconsistency between different studies frequently, but gained very little attention by scientists. There are many factors that can cause data variation and inconsistency during the process of microbiota study, in particular, sample storage conditions and subsequent sequencing process. Here, we systemically evaluated the impacts of six fecal sample storage conditions (including -80 {degrees}C, -80 {degrees}C with 70% ethanol (ET_-80 {degrees}C), 4{degrees}C with 70% ethanol (ET_4{degrees}C), and three commercial storage reagents including OMNIgene*GUT OMR-200 (GT), MGIEasy (MGIE), and Longsee (LS)), storage periods (1, 2 weeks or 6 months), and sequencing platform on gut microbiome profile using 16S rRNA gene sequencing. Our results suggested that -80{degrees}C is acceptable for fecal sample storage, and the addition of 70% ethanol offers some benefits. Meanwhile, we found that samples in ET_4 {degrees}Cand GT reagents are comparable, both introduced multi-dimensional variations. The use of MGIE resulted in the least alteration, while the greatest changes were observed in samples stored in LS reagents during the whole experiment. Finally, we also confirmed that variations caused by storage condition were larger than that of storage time and sequencing platform.\n\nIMPORTANCEIn the current study, we performed a multi-dimensional evaluation on the variations introduced by types of storage conditions, preservation period and sequencing platform on the basis of data acquired from 16S rRNA gene sequencing. The efficacy of preservation methods was comprehensively evaluated by DNA yield and quality, and {beta} diversity, relative abundance of the dominant bacteria and functional bacteria associated with SCFAs producing and BAs metabolism. Our results confirmed that variations introduced by storage condition were larger than that of storage periods and sequencing platform. Collectively, our study provided a comprehensive view to the impacts of storage conditions, storage times, and sequencing platform on gut microbial profile.

microbiology↗

bioRxiv2019

MMCA: a Web-based Server for the Microbiome and Metabolome Correlation Analysis

BackgroundIn the last decade, integrative studies of microbiome and metabolome have experienced exponential growth in understanding their impact on human health and diseases. However, analyzing the resulting multi-omics data and their correlations remains a significant challenge in current studies due to the lack of a comprehensive computational tool to facilitate data integration and interpretation. In this study, we have developed a microbiome and metabolome integrative analysis pipeline (M2IA) to meet the urgent needs for tools that effectively integrate microbiome and metabolome data to derive biological insights.\n\nResultsM2IA streamlines the integrative data analysis between metabolome and microbiome, including both univariate analysis and multivariate modeling methods. KEGG-based functional analysis of microbiome and metabolome are provided to explore their biological interactions within specific metabolic pathways. The functionality of M2IA was demonstrated using TwinsUK cohort data with 1116 fecal metabolites and 16s rRNA microbiome from 786 individuals. As a result, we identified two important pathways, i.e., the benzoate degradation and phosphotransferase system, were closely associated with obesity from both metabolome and microbiome.\n\nConclusionsM2IA is a public available web server (http://m2ia.met-bioinformatics.cn) with the capability to investigate the complex interplay between microbiome and metabolome, and help users to develop mechanistic hypothesis for nutritional and personalized therapies of diseases.

bioinformatics↗