Korea Research Institute of Bioscience and Biotechnology
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PRMT1 is required for the maintenance of mature β-cell identity
No full textLoss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet-induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.
Genomic signature of the standardized uptake value in 18F-fluorodeoxyglucose positron emission tomography in breast cancer
No full textThe standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10-4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.
Staphylococcus aureus specific FRET probe-based antibacterial susceptibility testing (SF-AST) by detection of micrococcal nuclease activity
No full textIn this study, we describe a simple and rapid antibacterial susceptibility testing (AST) method for Staphylococcus aureus called S. aureus specific fluorescence resonance energy transfer (FRET) probe-based AST (SF-AST), which is based on an S. aureus specific FRET probe (SF probe) that detects micrococcal nuclease (MNase) activity secreted from S. aureus. The SF-AST was tested with an S. aureus quality control (QC) strain against six relevant antibiotics, and the minimum inhibitory concentration (MIC) values obtained with the broth microdilution (BMD) method were compared, as a gold standard AST. Results were obtained with high accuracy in 4-6 h. The MIC for the methicillin resistance using 20 clinical S. aureus isolates of SF-AST showed 100% sensitivity, specificity, positive predictive value, and negative predictive value, as compared to BMD. Thus, the SF-AST method is a simple, rapid, and useful antibiotic resistance test for S. aureus, and it provides a basis for clinical treatment in a short time.
BiomeNet: a database for construction and analysis of functional interaction networks for any species with a sequenced genome
No full textMOTIVATION:
Owing to advanced DNA sequencing and genome assembly technology, the number of species with sequenced genomes is rapidly increasing. The aim of the recently launched Earth BioGenome Project is to sequence genomes of all eukaryotic species on Earth over the next 10？years, making it feasible to obtain genomic blueprints of the majority of animal and plant species by this time. Genetic models of the sequenced species will later be subject to functional annotation, and a comprehensive molecular network should facilitate functional analysis of individual genes and pathways. However, network databases are lagging behind genome sequencing projects as even the largest network database provides gene networks for less than 10% of sequenced eukaryotic genomes, and the knowledge gap between genomes and interactomes continues to widen.
RESULTS:
We present BiomeNet, a database of 95 scored networks comprising over 8 million co-functional links, which can build and analyze gene networks for any species with the sequenced genome. BiomeNet transfers functional interactions between orthologous proteins from source networks to the target species within minutes and automatically constructs gene networks with the quality comparable to that of existing networks. BiomeNet enables assembly of the first-in-species gene networks not available through other databases, which are highly predictive of diverse biological processes and can also provide network analysis by extracting subnetworks for individual biological processes and network-based gene prioritizations. These data indicate that BiomeNet could enhance the benefits of decoding the genomes of various species, thus improving our understanding of the Earth' biodiversity.
AVAILABILITY AND IMPLEMENTATION:
The BiomeNet is freely available at http://kobic.re.kr/biomenet/.
SUPPLEMENTARY INFORMATION:
Supplementary data are available at Bioinformatics online.
Transcriptional profiling of advanced urothelial cancer predicts prognosis and response to immunotherapy
No full textRecent investigations reported that some subtypes from the Lund or The Cancer Genome Atlas (TCGA) classifications were most responsive to PD-L1 inhibitor treatment. However, the association between previously reported subtypes and immune checkpoint inhibitor (ICI) therapy responsiveness has been insufficiently explored. Despite these contributions, the ability to predict the clinical applicability of immune checkpoint inhibitor therapy in patients remains a major challenge. Here, we aimed to re-classify distinct subtypes focusing on ICI responsiveness using gene expression profiling in the IMvigor 210 cohort (n = 298). Based on the hierarchical clustering analysis, we divided advanced urothelial cancer patients into three subgroups. To confirm a prognostic impact, we performed survival analysis and estimated the prognostic value in the IMvigor 210 and TCGA cohort. The activation of CD8+ T effector cells was common for patients of classes 2 and 3 in the TCGA and IMvigor 210 cohort. Survival analysis showed that patients of class 3 in the TCGA cohort had a poor prognosis, while patients of class 3 showed considerably prolonged survival in the IMvigor 210 cohort. One of the distinct characteristics of patients in class 3 is the inactivation of the TGFβ and YAP/TAZ pathways and activation of the cell cycle and DNA replication and DNA damage (DDR). Based on our identified transcriptional patterns and the clinical outcomes of advanced urothelial cancer patients, we constructed a schematic summary. When comparing clinical and transcriptome data, patients with downregulation of the TGFβ and YAP/TAZ pathways and upregulation of the cell cycle and DDR may be more responsive to ICI therapy.
NQO1 regulates pharmaco-behavioral effects of D-amphetamine in striatal dopaminergic system in mice
No full textThe NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.
Heterotrophic cultivation of Ettlia sp. based on sequential hydrolysis of Helianthus tuberosus and algal residue
No full textHeterotrophic cultivation of microalgae results in substantial productivity but requires significant nutrient input. Alternative sources of major nutrients such as C and N should be carefully selected to make heterotrophic production of microalgal biomass feasible. In this study, Helianthus tuberosus and lipid-extracted algae (LEA) were hydrolyzed with sulfuric acid to grow Ettlia sp. YC001. Hydrolysis of H. tuberosus with 0.3 N of sulfuric acid resulted in fructose yield of 0.51 g g？1 and glucose yield of 0.14 g g？1 at 80 °C in 1 h. Proteolysis of algal residue with 2 N of sulfuric acid resulted in amino acid yield of 0.38 g g？1 at 110 °C in 24 h. To simplify the production of hydrolysates, the hydrolysis conditions were combined to establish a tailored sequential hydrolysis process. Then, simultaneous neutralization and salt removal of the hydrolysates were done with barium hydroxide. Consequently, cultivation of Ettlia sp. with the diluted sequential hydrolysate of H. tuberosus and LEA successfully achieved 5.90 g L？1 d？1 of biomass productivity and 1.42 g L？1 d？1 of lipid productivity with Ettlia sp.
Requirement of the Cep57-Cep63 interaction for proper Cep152 recruitment and centriole duplication
No full textCep57 has been characterized as a component of a pericentriolar complex containing Cep63 and Cep152. Interestingly, Cep63 and Cep152 self-assemble into a pericentriolar cylindrical architecture, and this event is critical for the orderly recruitment of Plk4, a key regulator of centriole duplication. However, the way in which Cep57 interacts with the Cep63-Cep152 complex and contributes to the structure and function of Cep63-Cep152 self-assembly remains unknown. We demonstrate that Cep57 interacts with Cep63 through N-terminal motifs and associates with Cep152 via Cep63. Three-dimensional structured illumination microscopy (3D-SIM) analyses suggested that the Cep57-Cep63-Cep152 complex is concentrically arranged around a centriole in a Cep57-in and Cep152-out manner. Cep57 mutant cells defective in Cep63 binding exhibited improper Cep63 and Cep152 localization and impaired Sas6 recruitment for procentriole assembly, proving the significance of the Cep57-Cep63 interaction. Intriguingly, Cep63 fused to a microtubule (MT)-binding domain of Cep57 functioned in concert with Cep152 to assemble around stabilized MTs in vitro. Thus, Cep57 plays a key role in architecting the Cep63-Cep152 assembly around centriolar MTs and promoting centriole biogenesis. This study may offer a platform to investigate how the organization and function of the pericentriolar architecture are altered by disease-associated mutations found in the Cep57-Cep63-Cep152 complex.
Comparative proteomic analysis of host responses to Plasmodiophora brassicae infection in susceptible and resistant Brassica oleracea
No full textClubroot disease, caused by Plasmodiophora brassicae, is one of the most devastating diseases affecting members of the Brassicaceae family. It is difficult to control by chemical or cultural means, and the molecular mechanisms underlying interactions with Brassica oleracea (cabbage) remain poorly understood. Herein, we used a proteomic approach to investigate B. oleracea？P. brassicae interactions during the early phases of infection in above-ground tissues. Proteins were isolated from the aerial parts of clubroot-susceptible (CT-18) and -resistant (YCR) cabbage cultivars at 5？days after inoculation with P. brassicae or buffer (mock) and resolved by sodium dodecyl sulphate？polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis. A total of 24 differentially modulated proteins were identified in at least two biological replicates, and exhibited altered expression between mock and P. brassicae treatments and/or in the different cabbage cultivars. Most of the identified proteins are involved in oxidative stress, abscisic acid (ABA) metabolism, glucose-mediated signalling and responses to stimuli. Resistant YCR plants harboured an increased abundance of ABA-responsive protein, fructose-bisphosphate aldolase and glucose sensor interaction protein compared with CT-18 plants in both mock and P. brassicae-treated samples, suggesting that they may mediate basal defences against P. brassicae infection in YCR. Specifically, we observed that susceptible (CT-18) plants expressed higher levels of cobalamin-independent methionine synthase than YCR, which may enhance susceptibility of the host. Further investigation of the identified proteins will likely facilitate the identification of key molecular determinants, potentially improving clubroot disease resistance in future cabbage crop species.
The role of the VosA-repressed dnjA gene in development and metabolism in Aspergillus species
No full textThe DnaJ family of proteins (or J-proteins) are molecular chaperones that govern protein folding, degradation, and translocation in many organisms. Although J-proteins play key roles in eukaryotic and prokaryotic biology, the role of J-proteins in Aspergillus species is currently unknown. In this study, we characterized the dnjA gene, which encodes a putative DnaJ protein, in two Aspergillus species: Aspergillus nidulans and Aspergillus flavus. Expression of the dnjA gene is inhibited by the velvet regulator VosA, which plays a pivotal role in spore survival and metabolism in Aspergillus. The deletion of dnjA decreased the number of asexual spores (conidia), produced abnormal conidiophores, and reduced sexual fruiting bodies (cleistothecia) or sclerotia. In addition, the absence of dnjA caused increased sterigmatocystin or aflatoxin production in A. nidulans and A. flavus, respectively. These results suggest that DnjA plays a conserved role in asexual and sexual development and mycotoxin production in Aspergillus species. However, DnjA also plays a species-specific role; AniDnjA but not AflDnjA, affects conidial viability, trehalose contents, and thermal tolerance of conidia. In plant virulence assay, the infection ability of the ΔAfldnjA mutant decreased in the kernels, suggesting that DnjA plays a crucial role in the pathogenicity of A. flavus. Taken together, these results demonstrate that DnjA is multifunctional in Aspergillus species; it is involved in diverse biological processes, including fungal differentiation and secondary metabolism.