... and Evolution -- The Regulatory Apparatus Encoded in the DNA 2 -- The Genes and Gene Regulatory Components ... ... Inside the cis -Regulatory Module: Control Logic, and -- How Regulatory Environment is Transduced into ... ... Spatial -- Patterns of Gene Expression -- Operating Principles for cis -Regulatory Systems that -- Mediate ... ... Developmental Specification Events 26 -- Spatial Repression in cis -Regulatory specification 28 -- Two ... ... Changes that Make New Forms: Gene Regulatory Systems and the Evolution of Body Plans -- Some Examples ...
1st ed. xii, 261 s.
- MeSH
- Antigens, Bacterial MeSH
- Bacterial Proteins MeSH
- DNA, Bacterial analysis MeSH
- Virulence Factors MeSH
- Research Support as Topic MeSH
- Genomic Islands genetics MeSH
- Humans MeSH
- Gene Expression Regulation, Bacterial MeSH
- Streptococcus agalactiae genetics pathogenicity MeSH
- Streptococcus pneumoniae genetics MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
BACKGROUND: Integration of multi-omics data can provide a more complex view of the biological system consisting of different interconnected molecular components, the crucial aspect for developing novel personalised therapeutic strategies for complex diseases. Various tools have been developed to integrate multi-omics data. However, an efficient multi-omics framework for regulatory network inference at the genome level that incorporates prior knowledge is still to emerge. RESULTS: We present IntOMICS, an efficient integrative framework based on Bayesian networks. IntOMICS systematically analyses gene expression, DNA methylation, copy number variation and biological prior knowledge to infer regulatory networks. IntOMICS complements the missing biological prior knowledge by so-called empirical biological knowledge, estimated from the available experimental data. Regulatory networks derived from IntOMICS provide deeper insights into the complex flow of genetic information on top of the increasing accuracy trend compared to a published algorithm designed exclusively for gene expression data. The ability to capture relevant crosstalks between multi-omics modalities is verified using known associations in microsatellite stable/instable colon cancer samples. Additionally, IntOMICS performance is compared with two algorithms for multi-omics regulatory network inference that can also incorporate prior knowledge in the inference framework. IntOMICS is also applied to detect potential predictive biomarkers in microsatellite stable stage III colon cancer samples. CONCLUSIONS: We provide IntOMICS, a framework for multi-omics data integration using a novel approach to biological knowledge discovery. IntOMICS is a powerful resource for exploratory systems biology and can provide valuable insights into the complex mechanisms of biological processes that have a vital role in personalised medicine.
- MeSH
- Algorithms MeSH
- Bayes Theorem MeSH
- Gene Regulatory Networks MeSH
- Humans MeSH
- Colonic Neoplasms * MeSH
- Systems Biology methods MeSH
- DNA Copy Number Variations * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
To elucidate the physiological meaning of OmpR-dependent expression of invasin gene (inv) inhibition in Yersinia enterocolitica, the function of the EnvZ/OmpR regulatory pathway in osmoregulation of inv expression was analyzed in detail. The osmoregulation of inv expression was found to be a multifaceted process involving both OmpR-dependent and -independent mechanisms. Analysis of inv transcription in strains lacking OmpR or EnvZ proteins indicated that kinase EnvZ is not the only regulator of OmpR phosphorylation. Using the transcriptional inv::lacZ fusion in a heterologous system (Escherichia coli) we tried to clarify the role of OmpR in the inv regulatory circuit composed of negative (H-NS) and positive (RovA) regulators of inv gene transcription. We were able to show a significant increase in inv expression in E. coli ompR background under H-NS( Ecoli )-repressed condition. Moreover, H-NS-mediated inv repression was relieved when RovA of Y. enterocolitica was expressed from a plasmid. Furthermore, we showed that RovA may activate inv expression irrespective on the presence of H-NS protein. Using this strategy we showed that OmpR of Y. enterocolitica decrease RovA-mediated inv activation.
- MeSH
- Adhesins, Bacterial genetics MeSH
- Chromosomes, Bacterial genetics MeSH
- Bacterial Proteins genetics metabolism MeSH
- Escherichia coli genetics metabolism MeSH
- Gene Fusion MeSH
- Transcription, Genetic MeSH
- Lac Operon genetics MeSH
- Osmolar Concentration MeSH
- Promoter Regions, Genetic MeSH
- Gene Expression Regulation, Bacterial MeSH
- Trans-Activators genetics metabolism MeSH
- Yersinia enterocolitica genetics metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Bordetella pertussis is the causative agent of human whooping cough, a highly contagious respiratory disease which despite vaccination programs remains the major cause of infant morbidity and mortality. The requirement of the RNA chaperone Hfq for virulence of B. pertussis suggested that Hfq-dependent small regulatory RNAs are involved in the modulation of gene expression. High-throughput RNA sequencing revealed hundreds of putative noncoding RNAs including the RgtA sRNA. Abundance of RgtA is strongly decreased in the absence of the Hfq protein and its expression is modulated by the activities of the two-component regulatory system BvgAS and another response regulator RisA. Whereas RgtA levels were elevated under modulatory conditions or in the absence of bvg genes, deletion of the risA gene completely abolished RgtA expression. Profiling of the ΔrgtA mutant in the ΔbvgA genetic background identified the BP3831 gene encoding a periplasmic amino acid-binding protein of an ABC transporter as a possible target gene. The results of site-directed mutagenesis and in silico analysis indicate that RgtA base-pairs with the region upstream of the start codon of the BP3831 mRNA and thereby weakens the BP3831 protein production. Furthermore, our data suggest that the function of the BP3831 protein is related to transport of glutamate, an important metabolite in the B. pertussis physiology. We propose that the BvgAS/RisA interplay regulates the expression of RgtA which upon infection, when glutamate might be scarce, attenuates translation of the glutamate transporter and thereby assists in adaptation of the pathogen to other sources of energy.
- MeSH
- Bacterial Proteins genetics metabolism MeSH
- Bordetella pertussis genetics metabolism MeSH
- Glutamates metabolism MeSH
- Humans MeSH
- RNA, Small Untranslated genetics MeSH
- Gene Expression Regulation, Bacterial MeSH
- Signal Transduction * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In vitro fertilization (IVF) is fraught with problems and currently proteomics approaches are being tried out to examine the microenvironment of the follicle in order to assess biological and immunological parameters that may affect its development. Additionally, better understanding of reproductive process may help increase IVF birth rate per embryo transfer and at the same time avoid spontaneous miscarriages or life threatening conditions such as ovarian hyperstimulation syndrome. The primary aim of this study was to search for specific differences in protein composition of human follicular fluid (HFF) and plasma in order to identify proteins that accumulate or are absent in HFF. Depletion of abundant proteins combined with multidimensional protein fractionation allowed the study of middle- and lower-abundance proteins. Paired comparison study examining HFF with plasma/serum from women undergoing successful IVF revealed important differences in the protein composition which may improve our knowledge of the follicular microenvironment and its biological role. This study showed involvement of innate immune function of complement cascade in HFF. Complement inhibition and the presence of C-terminal fragment of perlecan suggested possible links to angiogenesis which is a vital process in folliculogenesis and placental development. Differences in proteins associated with blood coagulation were also found in the follicular milieu. Several specific proteins were observed, many of which have not yet been associated with follicle/oocyte maturation. These proteins together with their regulatory pathways may play a vital role in the reproductive process.
- MeSH
- Electrophoresis, Gel, Two-Dimensional MeSH
- Fertilization in Vitro MeSH
- Follicular Fluid chemistry metabolism MeSH
- Hemolysis MeSH
- Heparan Sulfate Proteoglycans analysis MeSH
- Immunoblotting MeSH
- Clusterin analysis MeSH
- Complement C4 analysis metabolism MeSH
- Complement C3 analysis metabolism MeSH
- Humans MeSH
- Proteome analysis metabolism MeSH
- Reproducibility of Results MeSH
- Cluster Analysis MeSH
- Signal Transduction MeSH
- Chromatography, High Pressure Liquid MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The mechanisms that regulate the maintenance of stem cell self-renewal versus differentiation are complex and remain mostly unknown. Understanding neurogenesis and neural cell differentiation presents a unique challenge for the treatment of nervous system disorders. To gain more insight into molecular mechanisms of the differentiation of neural cells, we combined the advantage of porcine fetal neural stem cells (NSCs) in vitro differentiation model and proteomic analysis. Using 2-DE followed by MS, we profiled constituent proteins of NSCs and their differentiated progenies at first and then indicated protein species that were significantly up- or down-regulated during the differentiation. The largest identified group of constituent proteins was related to RNA and protein metabolism and processing, including chaperones, and the second largest consisted of proteins involved in cell organization (cytoskeleton and annexins). Differentiation of neural cells was found to be accompanied by changes in the expression of proteins involved in DNA and RNA binding, mRNA processing and transport, stress responses, iron storage, and redox regulation. Additional immunoblot analysis verified the induction of alpha-B crystallin and heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1. Furthermore, immunocytochemistry demonstrated specific localization of alpha-B crystallin in the cytoplasm or nucleus of glial cells and confirmed cellular expression patterns of hnRNPs A1 and A2/B1. These findings represent a significant step towards understanding neural cell differentiation and identification of the regulatory proteins associated with this process.
- MeSH
- Electrophoresis, Gel, Two-Dimensional MeSH
- alpha-Crystallin B Chain metabolism MeSH
- Cell Differentiation physiology MeSH
- Financing, Organized MeSH
- Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism MeSH
- Mass Spectrometry MeSH
- Stem Cells cytology physiology MeSH
- Cells, Cultured MeSH
- Brain cytology MeSH
- Neurons cytology physiology MeSH
- Swine MeSH
- Proteomics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
OBJECTIVES: Clinical phenotyping and predicting treatment responses in SLE patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients. We aimed to translate existing transcriptomic data into simpler gene signatures suitable for daily clinical practice. METHODS: Real-time PCR of multiple genes from the IFN M1.2, IFN M5.12, neutrophil (NPh) and plasma cell (PLC) modules, followed by a principle component analysis, was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood-onset SLE cohorts (n = 101 and n = 34, respectively), and associations with clinical features were assessed. Disease activity was measured using Safety of Estrogen in Lupus National Assessment (SELENA)-SLEDAI. Cluster analysis subdivided patients into three mutually exclusive fingerprint-groups termed (1) all-signatures-low, (2) only IFN high (M1.2 and/or M5.12) and (3) high NPh and/or PLC. RESULTS: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Interestingly, in longitudinally collected samples, the PLC-signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution was reproduced in samples from an independent SLE cohort. CONCLUSIONS: The identified gene signatures were associated with disease activity and were indicated to be suitable tools for stratifying SLE patients into groups with similar activated immune pathways that may guide future treatment choices.
Directional organ growth allows the plant root system to strategically cover its surroundings. Intercellular auxin transport is aligned with the gravity vector in the primary root tips, facilitating downward organ bending at the lower root flank. Here we show that cytokinin signaling functions as a lateral root specific anti-gravitropic component, promoting the radial distribution of the root system. We performed a genome-wide association study and reveal that signal peptide processing of Cytokinin Oxidase 2 (CKX2) affects its enzymatic activity and, thereby, determines the degradation of cytokinins in natural Arabidopsis thaliana accessions. Cytokinin signaling interferes with growth at the upper lateral root flank and thereby prevents downward bending. Our interdisciplinary approach proposes that two phytohormonal cues at opposite organ flanks counterbalance each other's negative impact on growth, suppressing organ growth towards gravity and allow for radial expansion of the root system.
- MeSH
- Arabidopsis physiology MeSH
- Genome-Wide Association Study MeSH
- Cytokinins metabolism MeSH
- Plants, Genetically Modified physiology MeSH
- Genome, Plant genetics MeSH
- Gravitropism MeSH
- Plant Roots metabolism MeSH
- Oxidoreductases genetics metabolism MeSH
- Arabidopsis Proteins metabolism MeSH
- Proteolysis MeSH
- Plant Growth Regulators metabolism MeSH
- Systems Biology MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
