Biology subjects

Xu, F.

Publications and source records attributed to Xu, F..

At least 163 records · Page 9Linked to original sources

bioRxiv2019

Boron deficiency-induced root growth inhibition is mediated by BR signal regulation in Arabidopsis

Brassinosteroid (BR) is a pivotal phytohormone involved in regulating root development. Boron (B) is an essential micronutrient for plant growth and development, and root growth of plants is rapidly inhibited under B deficiency condition, but the mechanisms are still elusive. Here, we demonstrate that BR plays crucial roles in these processes. We identify BR-related processes underlying B deficiency at the physiological, genetic, molecular/cell biological and transcriptome levels, and provide strong evidences that B deficiency can affect BR signalling, thereby altering root growth. RNA-sequencing analysis reveals a high co-regulation between BR-regulated genes and B deficiency-responsive genes. We found that low B negatively regulates BR signalling to control BR signalling-dependent root elongation, bes1-D exhibits insensitivity to low B stress, and bri1-301 mutants fails to respond to B depletion. Exogenous eBL application can rescue the inhibition of root growth under B deficiency condition, and application of BR biosynthesis inhibitor BRZ aggravates root growth inhibition of wild-type under B deficiency condition. B deficiency reduces the nuclear signal of BES1. We further found that B deficiency reduces the accumulation of brassinolide (BL) by reducing BR6ox1 and BR6ox2 mRNA level to down-regulate BR signalling and modulate root elongation. Altogether, our results uncover a role of BR signalling in root elongation under B deficiency. One-sentence summaryB deficiency reduces the accumulation of brassinolide by reducing BR6ox1 and BR6ox2 mRNA level to down-regulate BR signalling and modulate root elongation.

physiology↗

bioRxiv2019

The compact genome of Giardia muris reveals important steps in the evolution of intestinal protozoan parasites

Diplomonad parasites of the genus Giardia have adapted to colonizing different hosts, most notably the intestinal tract of mammals. The human-pathogenic Giardia species, Giardia intestinalis, has been extensively studied at the genome and gene expression level, but no such information is available for other Giardia species. Comparative data would be particularly valuable for Giardia muris, which colonizes mice and is commonly used as a prototypic in vivo model for investigating host responses to intestinal parasitic infection. Here we report the draft-genome of G. muris. We discovered a highly streamlined genome, amongst the most densely encoded ever described for a nuclear eukaryotic genome. G. muris and G. intestinalis share many known or predicted virulence factors, including cysteine proteases and a large repertoire of cysteine-rich surface proteins involved in antigenic variation. Different to G. intestinalis, G. muris maintains tandem arrays of pseudogenized surface antigens at the telomeres, whereas intact surface antigens are present centrally in the chromosomes. The two classes of surface antigens engage in genetic exchange. Reconstruction of metabolic pathways from the G. muris genome suggest significant metabolic differences to G. intestinalis. Additionally, G. muris encodes proteins that might be used to modulate the prokaryotic microbiota. The responsible genes have been introduced in the Giardia genus via lateral gene transfer from prokaryotic sources. Our findings point to important evolutionary steps in the Giardia genus as it adapted to different hosts and it provides a powerful foundation for mechanistic exploration of host-pathogen interaction in the G. muris - mouse pathosystem.

evolutionary biology↗

bioRxiv2019

The maize heterotrimeric G-protein β subunit controls shoot meristem development and immune responses.

Heterotrimeric G-proteins are important transducers of receptor signaling, functioning in plants with CLAVATA receptors in control of shoot meristem size, and with pathogen associated molecular pattern (PAMP) receptors in basal immunity. However, whether specific members of the heterotrimeric complex potentiate crosstalk between development and defense, and the extent to which these functions are conserved across species, has not been addressed. Here we used CRISPR/Cas9 to knockout the maize G{beta} subunit gene, and found that the mutants were lethal, differing from Arabidopsis, where homologous mutants have normal growth and fertility. We show that lethality is not caused by a specific developmental arrest, but by autoimmunity. We used a genetic diversity screen to suppress the lethal g{beta} phenotype, and also identified a new maize G{beta} allele with weak autoimmune responses but strong development phenotypes. Using these tools, we show that G{beta} controls meristem size in maize, acting epistatically with G, suggesting that G{beta} and G function in a common signaling complex. Furthermore, we used an association study to show that natural variation in G{beta} influences maize kernel row number, an important agronomic trait. Our results demonstrate the dual role of G{beta} in immunity and development in a cereal crop, and suggest that it functions in crosstalk between these competing signaling networks. Therefore, modification of G{beta} has the potential to optimize the tradeoff between growth and defense signaling to improve agronomic production.\n\nSignificanceCereal crops, such as maize provide our major food and feed. Crop productivity has been significantly improved by selection of favorable architecture and development alleles, however crops are constantly under attack from pathogens, which severely limits yield due to a defense-growth tradeoff. Therefore, it is critical to identify key signaling regulators that control both developmental and immune signaling, to provide basic knowledge to maximize productivity. This work shows that the maize G protein {beta} subunit regulates both meristem development and immune signaling, and suggests that manipulation of this gene has the potential to optimize the tradeoff between yield and disease resistance to improve crop yields.

plant biology↗

bioRxiv2019

Gap junction coding innexin in Lymnaea stagnalis: sequence analysis and characterization in tissues and the central nervous system

Connections between neurons called synapses are the key components underlying all nervous system functions of animals and humans. However, important genetic information on the formation and plasticity of one type, the electrical (gap junction-mediated) synapse, is severely understudied, especially in invertebrates. In the present study, we set forth to identify and characterize the gap junction-encoding gene innexin in the central nervous system (CNS) of the mollusc pond snail Lymnaea stagnalis (L. stagnalis). With PCR, 3 and 5 RACE, and BLAST searches, we identified eight innexin genes in the L. stagnalis nervous system named Lst Inx1-8. Phylogenetic analysis revealed that the L. stagnalis innexin genes originated from a single copy in the common ancestor of molluscan species by multiple gene duplication events and have been maintained in L. stagnalis since they were generated. The paralogous innexin genes demonstrate distinct expression patterns among tissues. In addition, one paralog, Lst Inx1, exhibits heterogeneity in cells and ganglia, suggesting the occurrence of functional diversification after gene duplication. These results introduce possibilities to study an intriguing potential relationship between innexin paralog expression and cell-specific functional outputs such as heterogenic ability to form channels and exhibit synapse plasticity. The L. stagnalis CNS contains large neurons and a functionally defined network for behaviors; with the introduction of L. stagnalis in the gap junction field, we are providing novel opportunities to combine genetic research with direct investigation of functional outcomes at the cellular, synaptic, and behavioral levels.\n\nSummary StatementBy characterizing the gap junction gene innexin in Lymnaea stagnalis, we open opportunities for novel studies on the regulation, plasticity, and evolutionary function of electrical synapses throughout the animal kingdom.

neuroscience↗

bioRxiv2019

Glymphatic Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport

The presence of advection in neuropil is contested and solute transport is claimed to occur by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of glymphatic system (GS) transport revealed that solute speed was faster in cerebrospinal fluid (CSF) compared to grey and white matter. rOMT analysis also demonstrated 2-fold differences in regional particle speed within the brain parenchyma. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to transport in parenchyma. In rats with chronic hypertension, solute transport in perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normotension. Thus, the analytical framework of rOMT provides novel insights in local variation and dynamics of GS transport that may have implications for neurodegenerative diseases.

physiology↗

bioRxiv2019

A new GABAergic projection from the BNST onto accumbal parvalbumin neurons controls anxiety

The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-related avoidance when mice are under anxiogenic situations; sNAcPV neurons exhibited high excitability in chronically stressed mice model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic projections from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAcPV neurons; optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNSTGABA [Formula] sNAcPV synapses, which in turn explains the hyperexcitability of sNAcPV neurons on stressed models; therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to anxious state.\n\nOur findings reveal the coordination between BNST and NAc through an inhibitory architecture in controlling of anxiety-related response and provide a neurobiological basis for therapeutic interventions in pathological anxiety.

neuroscience↗

bioRxiv2019

The effects of carnosine pretreatment on the inflammatory response and the PI3K/Akt signaling pathway following hypoxia-ischemia in neonatal rats

An increasing number of studies have demonstrated that carnosine plays a neuroprotective role in many types of brain injury. We have previously shown that carnosine has both short-term and long-lasting neuroprotective effects in a hypoxia-ischemia(HI) rat model. In the mature brain, post-ischemia neuronal survival involves in activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, whether the activation of PI3K/Akt pathway also plays an important role in the immature brain still remain unclear.The goal of this study is to detect the effection of carnosine on inflammation response following HI, further evidencing neuroprotection of carnosine. We measured total Akt, phospho-Akt (p-AKT) and tumor necrosis factor receptor 1 (TNFR1) protein levels by western blot assay and tumor necrosis factor- (TNF-) and TNFR1 mRNA expression using real-time RT-PCR. We found the carnosine-pretreated group had statistically significant downregulation of TNF- mRNA levels 24 h after HI (P < 0.05). Similar results were observed when we measured TNFR1 mRNA levels both 24h and 72h after HI (P < 0.05). And the TNFR1 protein expression after HI was markedly decreased at 24 and 72 h post-HI in the carnosine-pretreated rats(P < 0.05). Nevertheless, the rats pretreated with carnosine showed a marked increase in p-Akt levels (P< 0.05). And the pro-apoptotic protein Bad was also examined using immunohistochemistry after 24 and 72 h of all groups. We found significantly fewer Bad-positive cells in the carnosine-pretreated group at each time point after HI (P < 0.05). These findings suggest that carnosine pretreatment inhibits the HI-induced inflammatory response, and neuroprotection mechanism of carnosine involved in activation of the PI3K/Akt signaling pathway.

neuroscience↗

bioRxiv2019

Maternal exposure to a mitochondrial toxicant results in life-long alterations in DNA methylation and gene expression in the offspring

Mitochondrial-driven alterations of the epigenome have been reported but whether they are relevant at the organismal level remain unknown. The viable yellow agouti mouse (Avy) is a powerful epigenetic biosensor model that reports on the DNA methylation status of the Avy locus through the coat color of the animals. Here we show that maternal exposure to rotenone, a potent mitochondrial complex I inhibitor, changes the DNA methylation status of the Avy locus and broadly affects the liver DNA methylome of the offspring. These effects were accompanied by altered gene expression programs that persisted throughout life. Mitochondrial dysfunction was present in the mothers but not in the offspring until 12 months of age, when electron transport and antioxidant defenses were impaired. These results highlight a putative novel role for mitochondria in nuclear epigenetic remodeling during development, raising fundamental questions about the long-term impact of mitochondrial dysfunction to health and disease.

genomics↗

bioRxiv2019

The Structural Basis of Indisulam-Mediated Recruitment of RBM39 to the DCAF15-DDB1-DDA1 E3 Ligase Complex

The anti-cancer agent Indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which Indisulam mediates DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-Indisulam-RBM39(RRM2) complex structure to 2.3 [A]. DCAF15 has a novel topology which embraces the RBM39(RRM2) domain largely via nonpolar interactions, and Indisulam binds between DCAF15 and RBM39(RRM2) and coordinates additional interactions between the two proteins. Studies with RBM39 point mutants and Indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39 and only these proteins were detectably downregulated in Indisulam-treated HCT116 cells. This work further explains how Indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade novel targets.

biophysics↗

bioRxiv2019

Three dimensional nanoscopy of whole cells and tissues with in situ point spread function retrieval

Single-molecule localization microscopy is a powerful tool in visualizing organelle structures, interactions, and protein functions in biological research. However, whole-cell and tissue specimens challenge the achievable resolution and depth of nanoscopy methods. As imaging depth increases, photons emitted by fluorescent probes, the sole source of molecular positions, were scattered and aberrated, resulting in image artifacts and rapidly deteriorating resolution. We propose a method to allow constructing the in situ 3D response of single emitters directly from single-molecule dataset and therefore allow pin-pointing single-molecule locations with limit-achieving precision and uncompromised fidelity through whole cells and tissues. This advancement expands the routine applicability of super-resolution imaging from selected cellular targets near coverslips to intra- and extra-cellular targets deep inside tissues. We demonstrate this across a range of cellular-tissue architectures from mitochondrial networks, microtubules, and nuclear pores in 2D and 3D cultures, amyloid-{beta} plaques in mouse brains to developing cartilage in mouse forelimbs.

biophysics↗

bioRxiv2019

Arabidopsis ECERIFERUM3 (CER3) Plays a Critical Role in Maintaining Hydration for Pollen-Stigma Recognition during Fertilization

ABSTRACTPlants distinguish the pollen grains that land on their stigmas, only allowing compatible pollen to fertilize female gametes. To analyze the underlying mechanism, conditional male-sterile mutations with affected pollen coat and disrupted pollen-stigma recognition were isolated and described. The mutant pollen failed to germinate, but germinated in vitro, suggesting that they are viable. In mutants, stigma cells that contacted their own pollen generated callose, a carbohydrate produced in response to foreign pollen. High humidity restored pollen hydration and successful fertilization, indicating defective dehydration in pollen-stigma interaction. Further analysis results from mixed pollination experiments demonstrated that the mutant pollen specifically lacked a functional pollen-stigma recognition system. The sterile plants lacked stem waxes and displayed postgenital fusion between aerial floral organs. In addition, the mutant pollen was deficient in long-chain lipids and had excess tryphine. Transmission electron microscopy observation showed that mutant pollen had almost the same surface structure as the wild type at bicellular pollen stage. However, abnormal plastoglobuli were observed in the plastids of the mutant tapetum, which was indicative of altered lipid accumulation. CER3 transcript was found in anther tapetum and microspores at development stage 9 while CER3-GFP fusion protein was localized to the cell plasma membrane. Our data reveal that CER3 is required for biosynthesis of tryphine lipids which play a critical role in maintaining hydration for pollen-stigma recognition during fertilization.

developmental biology↗

bioRxiv2019

Recombinase system-dependent copackaging strategy for highly efficient neurocircuit tracing

Mapping the detailed cell-type-specific input networks and neuronal projectomes are essential to understand brain function in normal and pathological states. However, several properties of current tracing systems, including labeling sensitivity, trans-synaptic efficiencies, reproducibility among different individuals and different Cre-driver animals, still remained unsatisfactory. Here, we developed MAP-ENVIVIDERS, a recombinase system-dependent vector mixing-based strategy for highly efficient neurocircuit tracing. MAP-ENVIVIDERS enhanced tracing efficiency of input networks across the whole brain, with over 10-fold improvement in diverse previously poor-labeled input brain regions and particularly, up to 70-fold enhancement in brainstem compared with the current standard rabies-virus-mediated systems. MAP-ENVIVIDERS was over 10-fold more sensitive for cell-type-specific labeling than previous strategies, enabling us to capture individual cell-type-specific neurons with extremely complex axonal branches and presynaptic axonal boutons, both about one order of magnitude than previously reported and considered. MAP-ENVIVIDERS provides powerful tools for deconstructing novel input/output circuitry towards functional studies and disorders-related mechanisms.

neuroscience↗

bioRxiv2019

A Single-Cell Immune Atlas of Triple Negative Breast Cancer Reveals Novel Immune Cell Subsets

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, which recently attracts great interest for immune therapeutic development. In this context, in-depth understanding of TNBC immune landscape is highly demanded. Here we report single-cell RNA sequencing results of 9683 tumor-infiltrated immune cells isolated from 14 treatment naive TNBC tumors, where 22 immune cell subsets, including T cells, macrophages, B cells, and DCs have been characterized. We identify a new T cell subset, CD8+CXCL8+ naive T cell, which associates with poor survival. A novel immune cell subset comprised of TCR+ macrophages, is found to be widely distributed in TNBC tumors. Further analyses reveal an up-regulation of molecules associated with TCR signaling and cytotoxicity in these immune cells, indicating TCR signaling activation. Altogether, our study provides a valuable resource to understand the immune ecosystem of TNBC. The novel immune cell subsets reported herein might be functionally important in cancer immunity.\n\nSIGNIFICANCEThis work demonstrates a single-cell transcriptome atlas of immune cells in treatment naive TNBC tumors, revealing novel immune cell subsets. This study provides a valuable resource to understand the immune ecosystem of TNBC, which will be helpful for the immunotherapeutic strategy design of TNBC.

immunology↗

bioRxiv2019

Super-resolution imaging reveals changes in Escherichia coli SSB localization in response to DNA damage.

The E. coli single stranded DNA binding protein (SSB) is essential to viability. It plays key roles in DNA metabolism where it binds to nascent single strands of DNA and to target proteins known as the SSB interactome. There are >2,000 tetramers of SSB per cell with perhaps 100-150 associated with genome at any one time, either at DNA replication forks or at sites of DNA repair. The remaining 1,900 tetramers could constantly diffuse throughout the cytosol or be associated with the inner membrane as observed for other DNA metabolic enzymes such as DnaA and RecA. To visualize SSB directly and to ascertain spatiotemporal changes in tetramer localization in response to DNA damage, SSB-GFP chimeras were visualized using a novel, super-resolution microscope optimized for visualization of prokaryotic cells. Results show that in the absence of DNA damage, SSB localizes to a small number of foci and the excess protein is observed associated with the inner membrane where it binds to the major phospholipids. Within five minutes following DNA damage, the vast majority of SSB disengages from the membrane and is found almost exclusively in the cell interior. Here, it is observed in a large number of foci, in discreet structures or, in diffuse form spread over the genome, thereby enabling repair events. In the process, it may also deliver interactome partners such as RecG or PriA to sites where their repair functions are required.

cell biology↗

bioRxiv2019

Methylomic profiles reveal sex-specific shifts in leukocyte composition associated with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men, develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific shifts in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, [~]450k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with a small but significant elevation in monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific peak shift reflects a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific shift in peripheral blood leukocyte composition that is detectable in methylomic profiles and that reflects long-standing changes associated with PTSD diagnosis.

genomics↗

bioRxiv2019

SSD1 suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications

The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) side-chains on uridines at the wobble position of cytosolic eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of Elongator not only leads to the lack of mcm5/ncm5 groups in tRNAs, but also a wide variety of phenotypes. Although the phenotypes are most likely caused by a translational defect induced by reduced functionality of the hypomodified tRNAs, the mechanism(s) underlying individual phenotypes are poorly understood. In this study, we show that the genetic background modulates the phenotypes induced by the lack of mcm5/ncm5 groups in Saccharomyces cerevisiae. We show that the stress-induced growth defects of Elongator mutants are stronger in the W303 than in the closely related S288C genetic background and that the phenotypic differences are caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. Moreover, the mutant ssd1 allele found in W303 cells is required for the reported histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. The difference at the SSD1 locus also partially explains why the simultaneous lack of mcm5 and 2-thio groups at wobble uridines is lethal in the W303 but not in the S288C background. Collectively, our results demonstrate that the SSD1 locus modulates phenotypes induced by the lack of Elongator-dependent tRNA modifications. Author SummaryModified nucleosides in the anticodon region of tRNAs are important for the efficiency and fidelity of translation. The Elongator complex promotes formation of several related modified uridine residues at the wobble position of eukaryotic tRNAs. In yeast, plants, worms, mice and humans, mutations in genes for Elongator subunits lead to a wide variety of different phenotypes. Here, we show that the genetic background modulates the phenotypic consequences of the inactivation of budding yeast Elongator. This background effect is largely a consequence of a polymorphism at the SSD1 locus, encoding a RNA binding protein that influences translation, stability and/or localization of mRNAs. We show that several phenotypes reported for yeast Elongator mutants are either significantly stronger or only detectable in strains harboring a mutant ssd1 allele. Thus, SSD1 is a suppressor of the phenotypes induced by the hypomodification of tRNAs.

genetics↗

bioRxiv2019

Streamlined low-input transcriptomics through EASY-RNAseq

High-throughput sequencing for transcriptome profiling is an increasingly accessible and important tool for biological research. However, accurate profiling of small cell populations remains challenging due to issues with gene detection sensitivity and experimental complexity. Here we describe a streamlined RNAseq protocol (EASY RNAseq) for sensitive transcriptome assessment starting from low amount of input materials. EASY RNAseq is technically robust enough for sequencing small pools of homogenous and heterogeneous cells, recovering higher numbers of genes and with a more even expression distribution pattern than other commonly used methods. Application of EASY RNAseq to single human embryos at the 8-cell stage was able to achieve detection of 70% protein-coding genes. This workflow may thus serve as a useful tool for sensitive interrogation of rare cell populations.

genomics↗

bioRxiv2019

Identification of 67 pleiotropic genes for seven autoimmune diseases using multivariate statistical analysis

Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery, this univariate approach has limitation in detecting complex genotype-phenotype correlations. It is essential to identify shared genetic risk factors acting through common biological mechanisms of autoimmune diseases with a multivariate analysis. In this study, the GWAS summary statistics including 41,274 single nucleotide polymorphisms (SNPs) located in 11,516 gene regions was analyzed to identify shared variants of seven autoimmune diseases using metaCCA method. Gene-based association analysis was used to refine the pleiotropic genes. In addition, GO term enrichment analysis and protein-protein interaction network analysis were applied to explore the potential biological function of the identified genes. After metaCCA analysis, 4,962 SNPs (P<1.21x10-6) and 1,044 pleotropic genes (P<4.34x10-6) were identified. By screening the results of gene-based p-values, we identified the existence of 27 confirmed pleiotropic genes and highlighted 40 novel pleiotropic genes which achieved significance threshold in metaCCA analysis and were also associated with at least one autoimmune disease in the VEGAS2 analysis. The metaCCA method could identify novel variants associated with complex diseases incorporating different GWAS datasets. Our analysis may provide insights for some common therapeutic approaches of autoimmune diseases based on the pleiotropic genes and common mechanisms identified. Author summaryAlthough previous researches have clearly indicated varying degrees of overlapping genetic sensitivities in autoimmune diseases, it has proven GWAS only explain small percent of heritability. Here, we take advantage of recent technical and methodological advances to identify pleiotropic genes that act on common biological mechanisms and the overlapping pathophysiological pathways of autoimmune diseases. After selection using multivariate analysis and verification using gene-based analyses, we successfully identified a total of 67 pleiotropic genes and performed the functional term enrichment analysis. In particularly, 27 genes were identified to be pleiotropic in previous different types of studies, which were validated by our present study. Forty significant genes (16 genes were associated with one disease earlier, and 24 were novel) might be the novel pleiotropic candidate genes for seven autoimmune diseases. The improved detection not only yielded the shared genetic components but also provided better understanding for exploring the potential common biological pathogenesis of these major autoimmune diseases.

genetics↗