Biology subjects

Yu, H.

Publications and source records attributed to Yu, H..

At least 433 records · Page 24Linked to original sources

bioRxiv2019

A full-proteome, interaction-specific characterization of mutational hotspots across human cancers

Rapid accumulation of cancer genomic data has led to the identification of an increasing number of mutational hotspots with uncharacterized significance. Here we present a biologically-informed computational framework that characterizes the functional relevance of all 1,107 published mutational hotspots identified in [~]25,000 tumor samples across 41 cancer types in the context of a human 3D interactome network, in which the interface of each interaction is mapped at residue resolution. Hotspots reside in network hub proteins and are enriched on protein interaction interfaces, suggesting that alteration of specific protein-protein interactions is critical for the oncogenicity of many hotspot mutations. Our framework enables, for the first time, systematic identification of specific protein interactions affected by hotspot mutations at the full proteome scale. Furthermore, by constructing a hotspot-affected network that connects all hotspot-affected interactions throughout the whole human interactome, we uncover genome-wide relationships among hotspots and implicate novel cancer proteins that do not harbor hotspot mutations themselves. Moreover, applying our network-based framework to specific cancer types identifies clinically significant hotspots that can be used for prognosis and therapy targets. Overall, we demonstrate that our framework bridges the gap between the statistical significance of mutational hotspots and their biological and clinical significance in human cancers.

bioinformatics↗

bioRxiv2019

Examining the relationships between phenotypic plasticity and local environments with genomic structural equation models

Environmental association analyses (EAA) seek to identify genetic variants associated with local adaptation by regressing local environmental conditions at collection sites on genome-wide polymorphisms. The rationale is that environmental conditions impose selective pressure on trait(s), and these traits are regulated in part by variation at a genomic level. Here, we present an alternative multivariate genomic approach that can be utilized when both phenotypic and environmental data are available for the population. This framework utilizes Bayesian networks (BN) to elucidate interdependancies between local environmental conditions and empirical phenotypes, and jointly estimates the direct and indirect genetic covariances between empirical phenotypes and environmental conditions using a mixed-effects structural equation model (SEM). Direct genomic covariance between empirical phenotypes and environmental conditions may provide insight into whether QTL that affect adaptation to an environmental gradient also affects the observed phenotype. To demonstrate the utility of this approach, we leveraged two existing datasets consisting of 55 climate variables for 1,130 Arabidopsis accessions and empirical phenotypes for fitness and phenology collected on 515 accessions in two common garden locations in Europe. BN showed that plasticity for fitness and phenology was highly dependant on local environmental conditions. Moreover, genomic SEM revealed relatively high positive genomic correlation between plasticity in fitness and environmental variables that describe the favorability of the local environment for plant growth, indicating the presence of common QTL or independent QTL that are tightly linked. We believe the frameworks presented in this manuscript can provide new insights into the genetic basis of local adaptation.

genomics↗

bioRxiv2019

Male accessory gland factors increased sex pheromone titres in the glands of Spodoptera litura female moths by inhibiting calling behavior

Moths are the most widely studied example of pheromones in animals. However, little is known about the mechanism of intrasexual and mating-related intersexual regulation of pheromone production and release in female moths. Our previous studies in Spodoptera litura found that mating induced a higher sex pheromone titre in the pheromone gland (PG) and mating or male accessory gland (MAG) extract suppressed female calling behavior. We therefore hypothesize that the inhibition of female calling behavior by mating or MAG factors likely suppresses the release of sex pheromones and thus results in a higher pheromone titre in the PG. To test this hypothesis, in the present study, we introduced an artificial calling behavior suppression treatment by gently knocking on and shaking the testing boxes contained moths once every 10 minutes. Results show that this treatment significantly increased pheromone titres in virgin or saline injected virgin females, and the increase rates are similar to those of mating and MAG extract treated ones. These results have suggested that the increase of sex pheromone titer in the female PG after mating in S. litura is due to the inhibition of female calling behavior by MAG factors. Moreover, results of this study also suggest that female calling behavior is positively correlated to pheromone release and likewise, the calling behavior and sex pheromone release in S. litura females are directly under the neural control, and modulated by molecular and environmental factors.

zoology↗

bioRxiv2019

Fibroblast growth factor-2 prevents synaptic pathology in minimal hepatic encephalopathy via NRG1/ErbB4 signaling

BackgroundMinimal hepatic encephalopathy (MHE) is implicated in the impairment of memory function. Fibroblast growth factor-2 (FGF2) is involved in modulating synaptic and neuronal formation. MethodsThe aim of this study is to examined the impacts of FGF2 on MHE pathology. Our study addressed whether FGF2 could trigger neuregulin-1 (NRG1) release to ameliorate synaptic impairment in MHE rats and in primary cultured neurons. ResultsThe results showed the decreased FGF2 expression in MHE brains. After treatment with FGF2, secreted neuregulin-1 (NRG1) and ErbB4 were increased, and the interaction of the 2 proteins was enhanced. Additionally, treatment with FGF2 or NRG1 induced synaptic formation, with increase in the activity of synapse and the density of dendritic spine, through Sirt1. NRG1 signaling was prevented by administration of FGF2, which acts through the FGFR1 in MHE rats. Finally, intracerebroventricular injection with FGF2 or NRG1 mitigated the impairment of synaptogenesis. ConclusionThe data suggest that FGF2 may be a promising latent therapeutic reagent for MHE pathogenesis.

neuroscience↗

bioRxiv2019

PI-Plat: A high-resolution image-based 3D reconstruction method to estimate growth dynamics of rice inflorescence traits

BackgroundRecent advances in image-based plant phenotyping have improved our capability to study vegetative stage growth dynamics. However, more complex agronomic traits such as inflorescence architecture (IA), which predominantly contributes to grain crop yield are more challenging to quantify and hence are relatively less explored. Previous efforts to estimate inflorescence-related traits using image-based phenotyping have been limited to destructive end-point measurements. Development of non-destructive inflorescence phenotyping platforms could accelerate the discovery of the phenotypic variation with respect to inflorescence dynamics and mapping of the underlying genes regulating critical yield components. ResultsThe major objective of this study is to evaluate post-fertilization development and growth dynamics of inflorescence at high spatial and temporal resolution in rice. For this, we developed the Panicle Imaging Platform (PI-Plat) to comprehend multi-dimensional features of IA in a non-destructive manner. We used 11 rice genotypes to capture multi-view images of primary panicle on weekly basis after the fertilization. These images were used to reconstruct a 3D point cloud of the panicle, which enabled us to extract digital traits such as voxel count and color intensity. We found that the voxel count of developing panicles is positively correlated with seed number and weight at maturity. The voxel count from developing panicles projected overall volumes that increased during the grain filling phase, wherein quantification of color intensity estimated the rate of panicle maturation. Our 3D based phenotyping solution showed superior performance compared to conventional 2D based approaches. ConclusionsFor harnessing the potential of the existing genetic resources, we need a comprehensive understanding of the genotype-to-phenotype relationship. Relatively low-cost sequencing platforms have facilitated high-throughput genotyping, while phenotyping, especially for complex traits, has posed major challenges for crop improvement. PI-Plat offers a low cost and high-resolution platform to phenotype inflorescence-related traits using 3D reconstruction-based approach. Further, the non-destructive nature of the platform facilitates analyses of the same panicle at multiple developmental time points, which can be utilized to explore the genetic variation for dynamic inflorescence traits in cereals.

plant biology↗

bioRxiv2019

A synthetic approach reveals a highly sensitive maize auxin response circuit

Auxin plays a key role across all land plants in growth and developmental processes. Although auxin signaling function has diverged and expanded, differences in the molecular functions of signaling components have largely been characterized in Arabidopsis thaliana. Here, we used the Auxin Response Circuit recapitulated in Saccharomyces cerevisiae (ARCSc) system to functionally annotate maize auxin signaling components, focusing on genes expressed during development of ear and tassel inflorescences. All 16 maize Auxin (Aux)/Indole-3-Acetic Acid (IAA) repressor proteins are degraded in response to auxin, with rates that depended on both receptor and repressor identity. When fused to the maize TOPLESS (TPL) homolog RAMOSA1 ENHANCER LOCUS2 (REL2), maize Aux/IAAs were able to repress AUXIN RESPONSE FACTOR (ARF) transcriptional activity. A complete auxin response circuit comprised of all maize components, including ZmAFB2/3 b1 maize AUXIN SIGNALING F-BOX (AFB) receptor, was found to be fully functional. The ZmAFB2/3 b1 auxin receptor was found to be more sensitive to hormone than AtAFB2 and allowed for rapid circuit activation upon auxin addition. These results validate the conserved role of predicted auxin response genes in maize, as well as provide evidence that a synthetic approach can facilitate broader comparative studies across the wide range of species with sequenced genomes. A synthetic maize auxin response circuit is recapitulated in Saccharomyces cerevisiae, revealing a highly sensitive auxin signaling network with functional homology to the Arabidopsis circuit.

plant biology↗

bioRxiv2019

A generalizable multivariate brain pattern for interpersonal guilt

Feeling guilty when we have wronged another is a crucial aspect of prosociality, but its neurobiological bases are elusive. Although multivariate patterns of brain activity show promise for developing brain measures linked to specific emotions, it is less clear whether brain activity can be trained to detect more complex social emotional states such as guilt. Here, we identified a distributed Guilt-Related Brain Signature (GRBS) across two independent neuroimaging datasets that used interpersonal interactions to evoke guilt. This signature discriminated conditions associated with interpersonal guilt from closely matched control conditions in a cross-validated training sample (N = 24; Chinese population) and in an independent test sample (N = 19; Swiss population). However, it did not respond to observed or experienced pain, or recalled guilt. Moreover, the GRBS only exhibited weak spatial similarity with other brain signatures of social affective processes, further indicating the specificity of the brain state it represents. These findings provide a step towards developing biological markers of social emotions, which could serve as important tools to investigate guilt-related brain processes in both healthy and clinical populations.

neuroscience↗

bioRxiv2019

Transcription imparts architecture, function, and logic to enhancer units

Distal enhancers remain one of the least understood regulatory elements with pivotal roles in development and disease. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites (TSSs) are robust predictors of enhancer activity with higher resolution and specificity than histone modifications. We show that active enhancer units are precisely delineated by active TSSs, validate that these boundaries are sufficient to capture enhancer function, and confirm that core promoter sequences are required for this activity. Finally, we assay pairs of adjacent units and find that their cumulative activity is best predicted by the strongest unit within the pair. Synthetic fusions of enhancer units demonstrate that adjacency imposes winner-takes-all logic, revealing a simple design for a maximum-activity filter of enhancer unit outputs. Together, our results define fundamental enhancer units and a principle of non-cooperativity between adjacent units.

genomics↗

bioRxiv2019

Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in bone-metastatic prostate cancer

Over 80% of prostate cancer (PCa) patients in the United States die with bone metastases. Second-line hormonal therapies, such as enzalutamide, improve overall survival in about 50% of patients with bone metastases, but almost all responsive patients eventually develop enzalutamide resistance. Our study showed that although enzalutamide significantly inhibited the tumor growth of subcutaneously or orthotopically grafted PCa C4-2B cells, it had no effect on the bone lesion development when C4-2B tumors were grafted in the bone, suggesting a crucial role of the microenvironment in enzalutamide resistance in PCa bone metastasis. We found that enzalutamide significantly decreased the amount of the TGFBR2 (TGF-{beta} type II receptor) in osteoblasts, both in vitro and in patient samples. The osteoblast-specific knockout of Tgfbr2 significantly induced bone metastasis. We showed that the enzalutamide-induced TGFBR2 decrease in osteoblasts was mediated by increased PTH1R (parathyroid hormone/parathyroid hormone-related peptide receptor), which resulted in TGFBR2 degradation, and that blocking PTH1R rescued the TGFBR2 decrease. Furthermore, we found that PTH1R up-regulation by enzalutamide was correlated with increased Pth1r promoter occupancy by transcription factor NR2F1. Our findings highlight a potential enzalutamide-resistance mechanism through TGFBR2 decrease in osteoblasts, thus suggesting future PTH1R-blocking approaches to overcome enzalutamide resistance in PCa bone metastasis.

cancer biology↗

bioRxiv2019

HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.

immunology↗

bioRxiv2019

Correlation between Serum Kisspeptin and Spermatogenic Function in Men

Kisspeptin along with its receptor GPR54 or KISS1R regulates the secretion of hormones involved in the hypothalamic-pituitary-testicular axis, which is one of the contributing factors of adolescent spermatogenesis. This study aimed to investigate the correlation between serum kisspeptin concentration and spermatogenic function, and its predictive value in azoospermia. We retrospectively analyzed data of 196 males who visited the Reproductive Medicine Center of Qilu Hospital of Shandong University from June-November 2018; 20 were fertile and 176 were infertile. The following semen tests were performed: serum kisspeptin level by enzyme immunoassay; and levels of follicle-stimulating and luteinizing hormones, and testosterone by chemiluminescence assay. Percutaneous testicular sperm aspiration was performed on males with azoospermia. Subjects were divided into 5 groups: azoospermia (group A: 22 men with obstructive azoospermia; group B: 54 men with non-obstructive azoospermia), oligospermia (group C: 56 men), infertility with normal semen concentration (group D: 44 men), and fertility with normal semen concentration (group E: 20 men). Kisspeptin levels in the fertile group were higher than those in the infertile group. Levels of serum hormones, testosterone, and kisspeptin correlated with sperm concentration, with the strongest correlation between kisspeptin and sperm concentration (correlation coefficient=0.692). Levels of kisspeptin in obstructive and non-obstructive azoospermia groups were analyzed using Receiver-Operating-Curve analysis. A serum kisspeptin level [≥]80.655 was classified as obstructive azoospermia; otherwise, the classification was non-obstructive azoospermia. Serum kisspeptin levels in the fertility group were significantly higher than that in the infertility group; this suggests kisspeptin may be associated with male fertility. Moreover, kisspeptin had a stronger correlation with sperm concentration than the hormones. A serum kisspeptin level of 80.655 can be used to differentiate obstructive and non-obstructive azoospermia.

physiology↗

bioRxiv2019

Golden pompano genome and embryo transcriptome shed light on regulation of minor ZGA gene on heart and vascular development

BACKGROUNDAngiogenesis is closely associated with angiogenesis-dependent diseases including cancers and ocular diseases. Anti-angiogenic therapeutics have been focusing on the (VEGF)/VEGFR signaling axis. However, the clinical resistance, high cost and frequent administration of anti-VEGF drugs make it urgent to discover novel angiogenic pathways.VE-PTP (ptprb) is a novel target with great anti-angiogenic potential. However, it is unclear whether upstream signaling pathways targeting VE-PTP exist in angiogenesis. METHODSWhole genome and embryo transcriptome sequencing were applied to discover the new gene nxhl. Transgenic zebrafish model, morpholino knockdown and small interfering RNA were used to explore the role of nxhl in angiogenesis both in vitro and in vivo. RNA pulldown, RIP and ChIRP-MS were used to identify interactions between RNA and protein. RESULTSWe discovered a novel zebrafish gene nxhl which is a homologue of the conserved gene nxh that co-expressed with some key genes essential for embryo development in vertebrate. Nxhl deletion causes angiogenesis defects in embryo. Moreover, nxhl is essential to mediate effects of angiogenesis in vivo and in vitro, and ptprb depletion duplicates the phenotypes of nxhl deficiency. Importantly, nxhl acts upstream of ptprb and regulates many extreme important ptprb-linked angiogenic genes by targeting VE-PTP (ptprb) through interactions with NCL. Notably, nxhl deletion decreases the phosphorylation of NCL T76 and increases the acetylation of NCL K88, suggesting nxhl may regulate downstream VE-PTP signaling pathways by mediation of NCL posttranslational modification. This is the first description of the interaction between nxhl and NCL, NCL and VE-PTP (ptprb), uncovering a novel nxhl-NCL-VE-PTP signaling pathway on angiogenesis regulation. CONCLUSIONSOur study identifies nxhl controlling angiogenesis by targeting VE-PTP through interactions with NCL, uncovering novel upstream controllers of VE-PTP. This nxhl-NCL-VE-PTP pathway may be a therapeutic target in the treatment of angiogenesis-dependent diseases. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIWe report a novel nxhl-NCL-VE-PTP signaling pathway that controls angiogenesis. C_LIO_LIWe for the first time demonstrate that nxhl interacts with NCL which simultaneously binds to VE-PTP that plays key roles on EC adherens junction, integrity and vascular homeostasis. C_LIO_LINxhl also controls some other crucial VE-PTP-linked downstream angiogenic genes (such as Tie2, VEGFaa, VEGFR2, Erbb2, S1pr1 and Hey2) which explain the phenotypes induced by the nxhl deficiency. C_LIO_LIOur study indicates the key role of nxhl on controlling angiogenesis as an upstream regulator of VE-PTP. C_LI What Are the Clinical Implications?O_LIThere are several ongoing researches investigating the utility of VE-PTP or NCL inhibitors on treatment of angiogenesis-dependent diseases including a range of cancers and nonneoplastic diseases, such as AMD, DME, RA and atherosclerosis. C_LIO_LITargeting the nxhl-NCL-VE-PTP pathway may facilitate therapeutic angiogenesis in patients with cancers or ocular diseases such as DME. C_LIO_LIOur study highlights the great potential of nxhl on anti-angiogenic therapeutics by targeting VE-PTP. C_LI

genomics↗

bioRxiv2019

LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best known tumor suppressors that promote homology recombination (HR) and arrest cell cycle at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.\n\nHighlightsO_LIDNA damage response downregulates LARP7 through BRCA1/BARD1\nC_LIO_LIBRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7\nC_LIO_LILARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complex\nC_LIO_LILARP7 disputes homology-directed repair that leads to tumor therapy resistance\nC_LI

molecular biology↗

bioRxiv2019

The effects of modified sialic acids on mucus and erythrocytes on influenza A virus HA and NA functions

Sialic acids (Sia) are the primary receptors for influenza viruses, and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C4, C7, C8, and C9 positions, and N-acetyl or N-glycolyl at C5. They can also vary in their linkages, including 2-3 or 2-6-linkages. Here, we analyzed the distribution of modified Sia in cells and tissues of wild-type mice, or in mice lacking cytidine 5-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) enzyme that synthesizes N-glycolyl modifications (Neu5Gc). We also examined the variation of Sia forms on erythrocytes and saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a great degree of variability in display of modified Sia between different species. IAV HA from different virus strains showed consistently reduced binding to both Neu5Gc and O-acetyl modified Sia; however, while IAV NA were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV, and may affect both pathogens and the normal flora of different mucosal sites.\n\nIMPORTANCESialic acids (Sia) are involved in many different cellular functions and are receptors for many pathogens. Sia come in many chemically modified forms but we lack a clear understanding of how they alter the interactions with microbes. Here we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably between different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

microbiology↗

bioRxiv2019

Selectivity and engineering of the sialoglycan-binding spectrum in Siglec-like adhesins

The Siglec-like Serine-Rich Repeat (SRR) adhesins mediate bacterial attachment to mammalian hosts via sialoglycan receptors. Here, we combine structural, computational, biochemical, and phylogenetic approaches to elucidate the determinants of the sialoglycan-binding spectrum across the family of Siglec-like SRR adhesins. We further identified mutable positions that disproportionately affect sialoglycan selectivity, as demonstrated by increases in binding to alternative ligands of 2- to 3-orders of magnitude. Biologically, these studies highlight how bacteria nimbly modulate the receptor interaction during coevolution of host and pathogen. These studies additionally created binding proteins specific for sialyl-T antigen or 6S-sialyl LewisX that can recognize glycosylation of human plasma proteins. The engineered binding proteins can facilitate the characterization of normal cellular glycan modifications or may be used as diagnostic tools in disease states with altered glycosylation.\n\nSignificanceThe ability of bacteria to bind selectively to host receptors underlies both commensalism and pathogenesis. Here, we identify the molecular basis for receptor selectivity in streptococci that bind to sialoglycan receptors. This revealed how to convert these adhesins into selective probes that measure triand tetrasacharides within the context of larger glycosylations. These probes that can be used in a laboratory with no specialized equipment and can be used to address biological questions relating to sialoglycan-dependent signaling and adhesion.

biochemistry↗

bioRxiv2019

Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection

The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC=\"FIGDIR/small/792200v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@18fed35org.highwire.dtl.DTLVardef@1e68b7org.highwire.dtl.DTLVardef@6cfbc8org.highwire.dtl.DTLVardef@1061a26_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA comprehensive single-cell resolution transcriptional landscape of mouse neutrophil maturation and fate decision under steady-state and bacterial infection conditions.\nC_LIO_LIThe pathogen clearance machinery in neutrophils is continuously and gradually built during neutrophil differentiation, maturation, and aging, driven by both known and uncharacterized transcription factors.\nC_LIO_LIThe three mature neutrophil subsets in peripheral blood, including a novel ISG-expressing subset, are derived from distinct bone marrow neutrophil precursors.\nC_LIO_LIBacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall neutrophil heterogeneity.\nC_LIO_LIBacterial infection-induced emergency granulopoiesis is mediated by augmented proliferation of early stage neutrophil progenitors and accelerated post-mitotic maturation.\nC_LI

immunology↗

bioRxiv2019

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output. Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a mutant heart as a possible consequence of Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1) activation, consistent with a recent intriguing report that CoQ may function as a natural ligand and partial agonist of Peroxisome Proliferator-Activated Receptor (PPAR) /{gamma}. Taken together, our study reveals a previously unknown function of a novel striated muscle-enriched mitochondrial protein Coq10a in regulating postnatal heart growth.

developmental biology↗

bioRxiv2019

KDDANet-a novel computational framework for systematic uncovering hidden gene interactions underlying known drug-disease associations

Many of genes mediating Known Drug-Disease Association (KDDA) are escaped from experimental detection. Identifying of these genes (hidden genes) is of great significance for understanding disease pathogenesis and guiding drug repurposing. Here, we presented a novel computational tool, called KDDANet, for systematic and accurate uncovering the hidden genes mediating KDDA from the perspective of genome-wide functional gene interaction network. KDDANet demonstrated the competitive performances in both sensitivity and specificity of identifying genes in mediating KDDA in comparison to the existing state-of-the-art methods. Case studies on Alzheimers disease (AD) and obesity uncovered the mechanistic relevance of KDDANet predictions. Furthermore, when applied with multiple types of cancer-omics datasets, KDDANet not only recapitulated known genes mediating KDDAs related to cancer, but also revealed novel candidates that offer new biological insights. Importantly, KDDANet can be used to discover the shared genes mediating multiple KDDAs. KDDANet can be accessed at http://www.kddanet.cn and the code can be freely downloaded at https://github.com/huayu1111/KDDANet.

bioinformatics↗