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Tian, C.

Publications and source records attributed to Tian, C..

At least 55 records · Page 3Linked to original sources
bioRxiv2022

Multi range ERK responses shape the proliferative trajectory of single cells following oncogene induced senescence

Oncogene-induced senescence (OIS) is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing OIS display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of the heterogeneity remain poorly understood. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the unique ERK-proliferation response. Altogether, our studies mapped the input-output relationships between ERK activity and proliferation providing important insights into how heterogeneity can be generated during OIS.

systems biology↗
bioRxiv2022

Analysis of sex differential genes at whole genome level reveals their organ- and chromosome-dependent expressions, regulations, and interactions

Males and females possess genomes that are almost identical but differ in morbidity, prevalence, severity, response to therapies and mortality of many diseases. We comprehensively analyzed gene expression data in seven tissues from BXD recombinant inbred (RI) mouse strains. We found that there were considerable differences in the numbers and functions among different tissues and between autosomal and sex chromosomes. Among sex differential genes, those on autosomal chromosomes mainly function to regulate metabolic pathways related to their host organs, while those on sex chromosomes mainly regulate nuclear proteins required for DNA replication or transcription during early development. Kidney possessed the fewest sex differential genes on sex chromosomes. The sexually dimorphic genes expressed on X chromosomes were all related to perception, while genes on the autosomal chromosomes were related to metabolism. These patterns of gene expression do not translate into similarity of protein structures, rather they are grouping with function.

cell biology↗
bioRxiv2022

A small-molecule lycorine derivative reveals Na+/K+-ATPase α3 as an anti-obesity target

Obesity remains a severe global public health challenge, with contemporary therapeutic approaches primarily focusing on appetite suppression. Here, we discovered HLY72, a lycorine-derived small molecule that potently counteracts obesity in mice at doses without affecting food intake, by promoting sympathetic activation-mediated lipolysis and thermogenesis in adipose tissues. Mass spectrometry identified Na+/K+-ATPase (NKA) 3, the brain-specific isoform, as HLY72s target. Only blood-brain barrier-permeable NKA inhibitors reproduce HLY72s anti-obesity effects, and resistance to HLY72 treatment occurs specifically in NKA 3 (not 1) knockin mice harboring a HLY72-binding mutation. Similar to the chemical inhibition by HLY72, genetic inhibition of NKA 3 also effectively protects mice from diet-induced obesity. These findings point NKA 3 as a potent anti-obesity drug target and highlight HLY72s potential in treating and preventing obesity independent of appetite control.

physiology↗
bioRxiv2022

A Unified Catalog of 19,251 Non-human Reference Species Genomes Provides New Insights into the Mammalian Gut Microbiomes

The gut microbiota is essential for host health and survival. Here, using samples from animals living in the Qinghai-Tibetan Plateau, we recovered 119,568 metagenome-assembled genomes (MAGs) that were clustered into 19,251 species-level genome bins (SGBs) of which most represent novel species. We present a novel mechanism shaping mammalian gut microbiomes using ancestral founder bacteria (AFB) as a core skeleton and recurring lineage-specific gains of microbial species that are transferred frequently among multiple hosts, not strictly limited by host phylogeny. Such lineage specific gains are responsible for increasing gut microbial diversity, maintaining functional stability, and endowing specific functions for host adaptions. Our analyses did not support the existence of co-phylogeny or co-speciation events between mammal hosts and their individual gut symbionts. The results presented in this study not only reveal novel unique gut microbial species and offer insight of value for understanding the diversity, stability, functionality of the mammalian gut microbiomes, and the co-evolution with their hosts, but also emphasize that animals living in extreme environments are a promising resource for the discovery of novel biological functions.

microbiology↗
bioRxiv2022

RNA Methylome Reveals the m6A-Mediated Regulation of Flavor Metabolites in Tea Leaves under Solar-Withering

Epitranscriptomic mark N6-methyladenosine (m6A) is the most predominant internal modification in RNAs, which plays pivotal roles in response to diverse stresses. Multiple environmental stresses caused by withering process can greatly influence the accumulation of specialized metabolites and the formation of tea flavor. However, little is known about the effects of m6A-mediated regulatory mechanism on flavor-related metabolisms in tea leaves. Here, we explored m6A-mediated regulatory mechanism and its impacts on flavonoid and terpenoid metabolisms under solar-withering using integrated RNA methylome and transcriptome. Dynamic changes in global m6A levels of tea leaves are mainly controlled by two m6A erasers (CsALKBH4A and CsALKBH4B) under solar-withering. Differentially methylated peak (DMP)-associated genes under different shading rates of solar-withering were identified and found to be enriched in terpenoid biosynthesis and spliceosome pathways. Further analyses indicated that CsALKBH4-driven RNA demethylation can not only directly affect the accumulation of volatile terpenoids by mediating the stability and abundance of terpenoid biosynthesis-related genes, but also indirectly influence the contents of flavonoids, catechins, and theaflavins via triggering the alternative splicing (AS)-mediated regulation. Our findings underscored a novel layer of epitranscriptomic gene regulation in tea flavor-related metabolic pathways and established a compelling link between m6A-mediated regulatory mechanism and the formation of high-quality flavor in tea leaves under solar-withering.

plant biology↗
bioRxiv2021

Elevated ozone concentration and nitrogen addition increase poplar rust severity by shifting the phyllosphere microbial community

The tropospheric ozone and nitrogen deposition are two major environmental pollutants. Numerous studies have focused on the negative impacts of elevated O3 and the complementary effect of soil N addition to tree physiological characteristics. However, it was notoriously ignored of how elevated O3 with N addition affect tree immunity in face of pathogen infection, as well as of the important roles of phyllosphere microbiome community in host-pathogen-environment interplay. Here, we examined the effects of elevated O3 and soil N addition on poplar leaf rust (Melampsora larici-populina) severity of two susceptible hybrid poplars (clone 107: Populus euramericana cv. 74/76; clone 546: P. deltoides {subseteq} P. cathayana) in Free-Air-Controlled-Environment plots, besides, the link between Mlp-susceptibility and changes in microbial community was determined using Miseq amplicon sequencing. Rust severity of clone 107 significantly increased under elevated O3 or N addition only, however, the negative impact of elevated O3 could be significantly alleviated when simultaneously conducting N addition, likewise, this trade-off was also found in its phyllosphere microbial -diversity responding to elevated O3 and N addition. However, the rust severity of clone 546 did not significantly differ in the cases of elevated O3 and N addition. Mlp infection altered microbial community composition and increased its sensitivity to elevated O3 assessed by significantly different abundance of taxa. Elevated O3 and N addition reduced the complexity of microbial community, which may explain the increased severity of poplar rust. These findings demonstrated that poplars need shifting phyllosphere microbial associations to optimize plant immunity in response to environmental changes. ImportanceExploitation of the interaction mechanisms between host plants and pathogens is the essential basis in disease control. However, while much was known about the molecular determinants in pathogenesis process in the past decades, less is known about the role of nonpathogenic microbial community in plant-pathogen interaction, especially when some host plants are currently encountering severe environmental stresses, such as elevated ozone concentration and superfluous nitrogen addition. Thus, we targeted at the widespread and detriment rust disease (poplar-poplar rust) to dissect the influences of elevated ozone and nitrogen addition on rust disease severity and how phyllosphere microbial groups interacting with both poplars and rust pathogen under these biotic stresses. Our findings could be used to prescribe ecological information about poplar plantation in areas with high levels of ozone pollution and better understand the important roles of microbiome in plant heath.

microbiology↗
bioRxiv2021

A Developmentally Prometastatic Niche to Hepatoblastoma in Neonatal Liver mediated by the Cxcl1/Cxcr2 Axis

Background and RationaleHepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development. MethodsHB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. ResultsWe found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers. ConclusionWe demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.

cancer biology↗
bioRxiv2021

Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Dextran Sodium Sulfate-Induced Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by multi-factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that Celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and the mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR preforms the protective effect. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation approaches. CSR administration significantly ameliorated DSS-induced colitis, as evidenced by the recovery of body weight and colon length, decreased disease activity index (DAI) score, as well as decreased intestinal permeability. CSR down-regulated the secretion of proinflammatory cytokines, upregulated the anti-inflammatory mediators, and improved the balances of Treg/Th1 and Treg/Th17 to maintain colonic immune homeostasis. However, the protective effects of CSR disappeared when the antibiotic cocktail was applied to deplete the gut microbiota, and the gut microbiota-mediated effect was confirmed by FMT. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and raised the metabolic productions of pyruvate and adenosine, which probably involve in gut microbiota mediated protective effect. In conclusion, CSR ameliorates colonic inflammation in a gut microbiota-dependent manner. The underlying protective mechanism is associated with the rectified Treg/Th1 and Treg/Th17 balance, and increased pyruvate and adenosine production. The study provided the solid evidence that CSR might be a promising therapeutic drug for UC.

microbiology↗
bioRxiv2021

Network pharmacology and chemoproteomics unveil the mechanism of Total Flavonoid Aglycones Extract inhibiting EMT in A549 cell line

Non-small cell lung cancer (NSCLC) is a worldwide disease with high morbidity and mortality, which is most derived from its metastasis. Some researches show that the epithelial-mesenchymal transition (EMT) process promotes lung cancer cells migration and invasion, leading to NSCLC metastasis. Total Flavonoid Aglycones Extract (TFAE) isolated from Scutellaria baicalensis was reported to inhibit tumor growth and induce apoptosis. In this study, we found that baicalein, wogonin, and oroxylin-A were the active compounds of TFAE. After reconstructing with these three compounds (baicalein (65.8%), wogonin (21.2%), and oroxylin-A (13.0%)), the reconstructed TFAE (reTFAE) present inhibitory effect on the EMT process of A549 cells. Then, bioinformatic technology was employed to elucidate the potential pharmacodynamic mechanism network of reTFAE. We identified the relationship between reTFAE and PI3K/Akt signaling pathways, with TWIST1 as the key protein. LY294002, the inhibitor of PI3K/Akt signaling pathway, and knock-down TWIST1 could significantly enhance the efficacy of reTFAE, with increasing expression of epithelial markers and decreasing expression of mesenchymal markers in A549 cells at the same time. Furthermore, stable isotope dimethyl-labeled proteomics technology was conducted to complement the follow-up mechanism that the EMT-inhibition process may be realized through glycolysis pathway. In conclusion, we claim that TWIST1-targeted flavonoids could provide a new strategy to inhibit EMT progress for the treatment of NSCLC.

pharmacology and toxicology↗
bioRxiv2021

Paradoxical Roles of Peritumoral Hepatic Stellate Cells in Liver Tumorigenesis in Mice: Retarding Tumor Growth and Promoting Tumor Dissemination

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on cancer-associated fibroblast residing within iCCA tumor mass, little is known about the fibrotic response from the tumor-surrounding liver and its role in iCCA development. In this study, we find a significant accumulation of peritumoral myofibroblasts (pMFs) in both patient iCCA and tumors from an iCCA orthotopic allograft mouse model. Using tumor and liver spheroid coculture we show that iCCA-liver interaction induces rapid pMF accumulation at the interface. We find pMFs placed around iCCA spheroids exert a strong suppressive effect on tumor cells growth, in contrast to the pro-proliferative effect of MFs mixed within tumor spheroids. However, prolonged iCCA-pMF interaction elicits tumor cell dissemination in vitro. We find an upregulation of Vcam1 in tumor cells in the early phase of iCCA-pMF interaction both in vitro and in vivo which is downregulated when tumor cells disseminate. Blocking Vcam1 activity in iCCA allograft mouse models slows primary tumor growth but lead to increased tumor metastasis. Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA, with the ability to suppress tumor growth but elicit tumor cell dissemination.

cancer biology↗
bioRxiv2021

Comprehensive molecular features of polycystic ovary syndrome revealed by transcriptome analysis of oocytes and cumulus cells

PCOS is typically characterized by polycystic ovarian morphology, hyperandrogenism, ovulatory dysfunction and infertility. Furthermore, PCOS patients undergoing ovarian stimulation have more oocytes, however, poor quality of oocytes lead to lower fertilization and implantation rates, decreased pregnancy and increased miscarriage rates. Our study suggests that global gene expression and cell to cell interactions of oocytes and CCs are significantly altered in women with PCOS. Noticeably, genes related to microtubules such as TUBB8 and TUBA1C are abnormally highly expressed in PCOS oocytes, reducing oocyte quality. The pattern of transposable element expression distinguishes PCOS from Control oocytes, implying the role of transposable elements in the occurrence of PCOS.

cell biology↗
bioRxiv2020

Analysis of Intermolt and Postmolt Transcriptomes Provides Insight into Molecular Mechanisms of the Red Swamp Crayfish, Procambarus Clarkii Molting

In the present study, we explored expression changes in the transcriptomes of two molting stages (post-molt (M) and Intermolt (NM)) of the red swamp crayfish. A total of 307608398 clean reads, with an average length of 145bp were obtained. Further clustering and assembly of the transcripts generated 139100 unigenes. The results were searched against the NCBI, NR, KEGG, Swissprot, and KOG databases, in order to annotate gene descriptions, associate them with gene ontology terms, and assign them to pathways. Several genes and other factors involved in a number of molecular events critical for molting, such as energy requirements, hormonal regulation, immune response, and exoskeleton formation were identified, evaluated, and characterized. The information presented here provides a basic understanding of the molecular mechanisms underlying the crayfish molting process, with respect to energy requirements, hormonal regulation, immune response, and skeletal related activities during post-molt stage and the intermolt stage.

genomics↗
bioRxiv2020

Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

cancer biology↗
bioRxiv2020

Single-nucleus RNA-seq resolves spatiotemporal developmental trajectories in the tomato shoot apex

Single cell transcriptomics is revolutionizing our understanding of development and response to environmental cues1-3. Recent advances in single cell RNA sequencing (scRNA-seq) technology have enabled profiling gene expression pattern of heterogenous tissues and organs at single cellular level and have been widely applied in human and animal research4,5. Nevertheless, the existence of cell walls significantly encumbered its application in plant research. Protoplasts have been applied for scRNA-seq analysis, but mostly restricted to tissues amenable for wall digestion, such as root tips6-10. However, many cell types are resistant to protoplasting, and protoplasting may yield ectopic gene expression and bias proportions of cell types. Here we demonstrate a method with minimal artifacts for high-throughput single-nucleus RNA sequencing (snRNA-Seq) that we use to profile tomato shoot apex cells. The obtained high-resolution expression atlas identifies numerous distinct cell types covering major shoot tissues and developmental stages, delineates developmental trajectories of mesophyll cells, vasculature cells, epidermal cells, and trichome cells. In addition, we identify key developmental regulators and reveal their hierarchy. Collectively, this study demonstrates the power of snRNA-seq to plant research and provides an unprecedented spatiotemporal gene expression atlas of heterogeneous shoot cells.

plant biology↗
bioRxiv2020

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected ten millions of people across the globe, and massive mutations in virus genome have occurred during the rapid spread of this novel coronavirus. Variance in protein sequence might lead to change in protein structure and interaction, then further affect the viral physiological characteristics, which could bring tremendous influence on the pandemic. In this study, we investigated 18 non-synonymous mutations in SARS-CoV-2 genome which incidence rates were all [≥]1% as of July 15th, 2020, then modeled the mutated protein structures and compared them with the reference ones. The results showed that four types of mutations could cause dramatic changes in protein structures (RMSD [≥]5.0 [A]), which were Q57H and G251V in open reading frames 3a (ORF3a), S194L and R203K/G204R in nucleocapsid (N). Next, we found that these mutations could affect the binding affinity of intraviral protein interactions. In addition, the hot spots within these docking complexes were altered, among which the mutation Q57H was involved in both Orf3a-Orf8 and Orf3a-S protein interactions. Besides, these mutations were widely distributed all over the world, and their occurrences fluctuated as time went on. Notably, the incidences of R203K/G204R in N and Q57H in Orf3a were both over 50% in some countries. Overall, our findings suggest that SARS-CoV-2 mutations can change viral protein structure, binding affinity and hot spots of the interface, thereby may have impacts on SARS-CoV-2 transmission, diagnosis and treatment of COVID-19.

microbiology↗
bioRxiv2020

Identification of microbial markers across populations in early detection of colorectal cancer

Several studies have investigated the association between microbial and colorectal cancer (CRC). However, the replicable markers for early stage adenoma diagnosis across multiple populations remain elusive. Here, a meta-analysis of six studies, comprising a total of 1057 fecal samples, was performed to identify candidate markers. By adjusting the potential confounders, 11 and 26 markers (P<0.05) were identified and separately applied into constructing Random Forest classifier models to discriminate adenoma from control, and adenoma from CRC, achieving robust diagnostic accuracy with AUC = 0.80 and 0.89, respectively. Moreover, these markers demonstrated high diagnostic accuracy in independent validation cohorts. Pooled functional analysis and targeted qRT-PCR based genetic profiles reveal that the altered microbiome triggers different pathways of ADP-heptose and menaquinone biosynthesis (P<0.05) in adenoma vs. control and adenoma vs. CRC sequences respectively. The combined analysis of heterogeneous studies confirm adenoma-specific but universal markers across multi-populations, which improves early diagnosis and prompt treatment of CRC.

pathology↗
bioRxiv2020

Identification of the keystone species in non-alcoholic fatty liver disease by causal inference and dynamic intervention modeling

ObjectiveKeystone species are required for the integrity and stability of an ecological community, and therefore, are potential intervention targets for microbiome related diseases. DesignHere we describe an algorithm for the identification of keystone species from cross-sectional microbiome data of non-alcoholic fatty liver disease (NAFLD) based on causal inference theories and dynamic intervention modeling (DIM). ResultsEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, were identified by our algorithm, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome with 92.3% recovery. These keystone species regulate intestinal amino acids metabolism and acid-base environment to promote the growth of the butyrate-producing Lachnospiraceae and Ruminococcaceae species. ConclusionOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. SUMMARYWhat is already known about this subject? O_LINon-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disease whose pathogenesis remains unclear. C_LIO_LIDysbiosis in the gut microbiota affects the initiation and development of NAFLD, but the mechanisms is yet to be established. C_LIO_LIKeystone species represent excellent candidate targets for gut microbiome-based interventions, as they are defined as the species required for the integrity and stability of the ecological system. C_LI What are the new findings? O_LINAFLD showed significant dysbiosis in butyrate-producing Lachnospiraceae and Ruminococcaceae species. C_LIO_LIMicrobial interaction networks were constructed by the novel algorithm with causal inference. C_LIO_LIKeystone species were identified form microbial interaction networks through dynamic intervention modeling based on generalized Lotka-Volterra model. C_LIO_LIEight keystone species of NAFLD with the highest potential for restoring the microbial composition were identified. C_LI How might it impact on clinical practice in the foreseeable future? O_LIAn algorithm for the identification of keystone species from cross-sectional microbiome data based on causal inference theories and dynamic intervention modeling. C_LIO_LIEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome. C_LIO_LIOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. C_LI

bioinformatics↗