Refine
Has Fulltext
- yes (30)
Is part of the Bibliography
- yes (30)
Year of publication
Document Type
- Journal article (30)
Language
- English (30)
Keywords
- DNA methylation (4)
- Candida albicans (2)
- ELISPOT (2)
- bisulfite pyrosequencing (2)
- exome sequencing (2)
- transcriptome (2)
- (classical and atypical) Werner syndrome (1)
- 3D modeling (1)
- ANOVA (1)
- Aspergillus fumigatus (1)
- Autism (1)
- Autism spectrum disorders (1)
- B cell receptors (1)
- CD4 (1)
- CD8 (1)
- CDC14A (1)
- Chlamydia pneumoniae (1)
- DFNB32 (1)
- DFNB68 (1)
- DNA damage (1)
- DNA methylation dynamics (1)
- Down syndrome (1)
- Environment (1)
- Epigenetics (1)
- Fetal brain development (1)
- Fourthcorner analysis (1)
- Frontal cortex (1)
- Functional modules (1)
- Gene-expression (1)
- Genome (1)
- High-throughput data (1)
- Human prefrontal cortex (1)
- IFN-γ (1)
- IL-17 (1)
- IL-2 (1)
- IL-4 (1)
- IL-5 (1)
- Integrated network analysis (1)
- LC-MS/MS (1)
- MITE (1)
- Metabolic pathways (1)
- Metabolic profiles (1)
- Methylome (1)
- Microarray analysis (1)
- Milnesium tardigradum (1)
- Multivariate analysis (1)
- Neisseria gonorrhoeae (1)
- Neisseria meningitidis (1)
- Normal Distribution (1)
- Ordination methods (1)
- Pakistan (1)
- Patterns (1)
- RLQ analysis (1)
- RNA extraction (1)
- RNA-Seq analysis (1)
- S1PR2 (1)
- Schizophrenia (1)
- Staphylococcus aureus (1)
- T cells (1)
- T-cells (1)
- Transcription (1)
- Transcriptomics (1)
- Trend test (1)
- VASP (1)
- Vasodilatator-stimuliertes Phosphoprotein (1)
- Visualization (1)
- abscisic acid (ABA) (1)
- age-related differentially methylated regions (ageDMRs) (1)
- alu elements (1)
- alzheimers disease (1)
- apixaban (1)
- aspergillus fumigatus (1)
- autosomal recessive hearing loss (1)
- autosomal recessive non-synstromic hearing loss (1)
- autotoxicity (1)
- bark beetles (1)
- behavior (1)
- bioinformatics and computational biology (1)
- blood (1)
- cancer treatment (1)
- candida genome database (1)
- cascade (1)
- cell death (1)
- cell wall (1)
- classification (1)
- communities (1)
- community structures (1)
- comparative genomics (1)
- complex traits (1)
- computational prediction (1)
- conifers (1)
- consanguinity (1)
- cryptic (1)
- cyclic nucleotide signaling (1)
- cytokines (1)
- cytotoxicity (1)
- database (1)
- decay (1)
- denritic cells (1)
- diagnostic accuracy (1)
- direct oral anticoagulants (1)
- direct thrombin inhibitor (1)
- disruption project (1)
- ecology (1)
- epigenetics (1)
- epithelial cells (1)
- european beech forests (1)
- expression signature (1)
- factor XA inhibitor (1)
- fetal brain development (1)
- fetal cord blood (1)
- fetal programming (1)
- fibroblasts (1)
- flies (1)
- forests (1)
- frameshift (1)
- frontal cortex (1)
- functional analysis (1)
- functional modules (1)
- gating (1)
- gene expression (1)
- gene regulation (1)
- genetic diagnosis (1)
- genetic loci (1)
- genetic variation (1)
- genetics (1)
- genome sequencing (1)
- genome-wide linkage analysis (1)
- genomic libraries (1)
- gestational diabetes mellitus (1)
- glycophyte Arabidopsis (1)
- guard cell (1)
- halophyte Thellungiella/Eutrema (1)
- hearing loss (1)
- heat shock response (1)
- host cells (1)
- human (1)
- immune receptors (1)
- immune response (1)
- insulin treatment (1)
- interactome (1)
- interolog (1)
- interspecies comparison (1)
- ion transport (1)
- isothiocyanates (1)
- kinase signaling (1)
- macrophages (1)
- mammalian male germline (1)
- management (1)
- markers (1)
- metabolism (1)
- metastasis (1)
- methylation (1)
- methylation array (1)
- mixed hearing loss (1)
- modules (1)
- molecular cloning (1)
- mouse (1)
- mustard oil bomb (1)
- natural variation (1)
- neisseria meningitidis (1)
- network (1)
- network analysis (1)
- network inference (1)
- networks (1)
- neutrophils (1)
- non-sense mediated mRNA decay (1)
- normal distribution (1)
- norway spruce (1)
- oaks (1)
- painful (1)
- paternal age effect (1)
- pathogen-host interaction (PHI) (1)
- pathogenicity (1)
- performance liquid chromatography (1)
- phosphoproteome (1)
- pines (1)
- platelet (1)
- potential role (1)
- predation (1)
- premature aging (1)
- protein interaction database (1)
- protein-interaction networks (1)
- protein-protein interaction (1)
- proteome (1)
- protocadherin gamma cluster (1)
- quantification (1)
- rare (1)
- reactive electrophilic species (1)
- redox homeostasis (1)
- relA (1)
- salt stress (1)
- segmental progeria (1)
- sequence assembly tools (1)
- serum (1)
- set (1)
- signaling (1)
- silico model (1)
- sky kinases (1)
- software (1)
- soil (1)
- species-specific epigenetic marks (1)
- sperm DNA methylation (1)
- spiders (1)
- splicing (1)
- spot size (1)
- stability (1)
- statistics (1)
- stomata (1)
- stringent response (1)
- substrate quality (1)
- sulforaphane (1)
- survival (1)
- systems biology (1)
- t-Test (1)
- temperature (1)
- throat (1)
- transcription deficiency (1)
- transcriptional regulation (1)
- transposable elements (1)
- trees (1)
- trisomy 21 (1)
- validation (1)
- virulenceregulatory evolution (1)
- whole exome sequencing (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (29)
- Institut für Humangenetik (15)
- Institut für Hygiene und Mikrobiologie (2)
- Julius-von-Sachs-Institut für Biowissenschaften (2)
- Institut für Experimentelle Biomedizin (1)
- Institut für Klinische Biochemie und Pathobiochemie (1)
- Institut für Molekulare Infektionsbiologie (1)
- Medizinische Klinik und Poliklinik II (1)
- Rudolf-Virchow-Zentrum (1)
Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.
A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here.
Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.
Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.
Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.
Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/or sequences covaried with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance- associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hairlike organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.
Background:
Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies.
Methods and results:
Using Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM.
Conclusions:
Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.
In Brassicaceae, tissue damage triggers the mustard oil bomb i.e., activates the degradation of glucosinolates by myrosinases leading to a rapid accumulation of isothiocyanates at the site of damage. Isothiocyanates are reactive electrophilic species (RES) known to covalently bind to thiols in proteins and glutathione, a process that is not only toxic to herbivores and microbes but can also cause cell death of healthy plant tissues. Previously, it has been shown that subtoxic isothiocyanate concentrations can induce transcriptional reprogramming in intact plant cells. Glutathione depletion by RES leading to breakdown of the redox potential has been proposed as a central and common RES signal transduction mechanism. Using transcriptome analyses, we show that after exposure of Arabidopsis seedlings (grown in liquid culture) to subtoxic concentrations of sulforaphane hundreds of genes were regulated without depletion of the cellular glutathione pool. Heat shock genes were among the most highly up-regulated genes and this response was found to be dependent on the canonical heat shock factors A1 (HSFA1). HSFA1-deficient plants were more sensitive to isothiocyanates than wild type plants. Moreover, pretreatment of Arabidopsis seedlings with subtoxic concentrations of isothiocyanates increased resistance against exposure to toxic levels of isothiocyanates and, hence, may reduce the autotoxicity of the mustard oil bomb by inducing cell protection mechanisms.
Objective
The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the intrinsic correlation structure of complex annotated gene expression data and discover the covariates that jointly affect expression patterns.
Results
The Bioconductor package covRNA provides a convenient and fast interface for testing and visualizing complex relationships between sample and gene covariates mediated by gene expression data in an entirely unsupervised setting. The relationships between sample and gene covariates are tested by statistical permutation tests and visualized by ordination. The methods are inspired by the fourthcorner and RLQ analyses used in ecological research for the analysis of species abundance data, that we modified to make them suitable for the distributional characteristics of both, RNA-Seq read counts and microarray intensities, and to provide a high-performance parallelized implementation for the analysis of large-scale gene expression data on multi-core computational systems. CovRNA provides additional modules for unsupervised gene filtering and plotting functions to ensure a smooth and coherent analysis workflow.
Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response.
Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype.