An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32959 | GEO | 2012/11/09
SECONDARY ACCESSION(S): PRJNA146407
REPOSITORIES: GEO
Similar Datasets
Project description:The aim of this dataset was to study in detail the transcription kinetics initiated by cytokines IL-12 and IL-4 in early differentiation of Th1 and Th2 cells, respectively. Total RNA obtained from activated and IL-12 or IL-4 & anti-IL-12 treated cord blood CD4+ T cells, 12, 24, 48, and 72 hours after initiation of the cultures, compared to cells which were only activated. 37 samples were analyzed from three biological replicates of the culture. Several (26) of the Samples in this Series represent a re-analysis of CEL files originally submitted as GEO Series GSE17974. Please see associations on each Sample record.
2012-11-09 | E-GEOD-32959 | biostudies-arrayexpress
Project description:BACKGROUND: A proper balance between different T helper (Th) cell subsets is necessary for normal functioning of the adaptive immune system. Revealing key genes and pathways driving the differentiation to distinct Th cell lineages provides important insight into underlying molecular mechanisms and new opportunities for modulating the immune response. Previous computational methods to quantify and visualize kinetic differential expression data of three or more lineages to identify reciprocally regulated genes have relied on clustering approaches and regression methods which have time as a factor, but have lacked methods which explicitly model temporal behavior. RESULTS: We studied transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation. To identify genes that exhibit distinct lineage commitment dynamics and are specific for initiating differentiation to different Th cell subsets, we developed a novel computational methodology (LIGAP) allowing integrative analysis and visualization of multiple lineages over whole time-course profiles. Applying LIGAP to time-course data from multiple Th cell lineages, we identified and experimentally validated several differentially regulated Th cell subset specific genes as well as reciprocally regulated genes. Combining differentially regulated transcriptional profiles with transcription factor binding site and pathway information, we identified previously known and new putative transcriptional mechanisms involved in Th cell subset differentiation. All differentially regulated genes among the lineages together with an implementation of LIGAP are provided as an open-source resource. CONCLUSIONS: The LIGAP method is widely applicable to quantify differential time-course dynamics of many types of datasets and generalizes to any number of conditions. It summarizes all the time-course measurements together with the associated uncertainty for visualization and manual assessment purposes. Here we identified novel human Th subset specific transcripts as well as regulatory mechanisms important for the initiation of the Th cell subset differentiation.
| S-EPMC3526425 | biostudies-other
Project description:Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory-demyelinating events in the central nervous system. Despite more than 40 years of MS research its aetiology remains unknown. This study aims to identify the most frequently reported and consistently regulated molecules in MS in order to generate molecular interaction networks and thereby leading to the identification of deregulated processes and pathways which could give an insight of the underlying molecular mechanisms of MS. Driven by an integrative systems biology approach, gene-expression profiling datasets were combined and stratified into "Non-treated" and "Treated" groups and additionally compared to other disease patterns. Molecular identifiers from dataset comparisons were matched to our Multiple Sclerosis database (MuScle; www.padb.org/muscle ). From 5079 statistically significant molecules, correlation analysis within groups identified a panel of 16 high-confidence genes unique to the naïve MS phenotype, whereas the "Treated" group reflected a common pattern associated with autoimmune disease. Pathway and gene-ontology clustering identified the Interferon gamma signalling pathway as the most relevant amongst all significant molecules, and viral infections as the most likely cause of all down-stream events observed. This hypothesis-free approach revealed the most significant molecular events amongst different MS phenotypes which can be used for further detailed studies.
| S-EPMC5884799 | biostudies-literature
Project description:Maximisation of the ratio of normal tissue preservation and tumour cell reduction is the main concept of radiotherapy alone or combined with chemo-, immuno- or biologically targeted therapy. The foremost parameter influencing this ratio is radiation sensitivity and its modulation towards a more efficient killing of tumour cells and a better preservation of normal tissue at the same time is the overall aim of modern therapy schemas. Nevertheless, this requires a deep understanding of the molecular mechanisms of radiation sensitivity in order to identify its key players as potential therapeutic targets. Moreover, the success of conventional approaches that tried to statistically associate altered radiation sensitivity with any molecular phenotype such as gene expression proofed to be somewhat limited since the number of clinically used targets is rather sparse. However, currently a paradigm shift is taking place from pure frequentistic association analysis to the rather holistic systems biology approach that seeks to mathematically model the system to be investigated and to allow the prediction of an altered phenotype as the function of one single or a signature of biomarkers. Integrative systems biology also considers the data from different molecular levels such as the genome, transcriptome or proteome in order to partially or fully comprehend the causal chain of molecular mechanisms. An example for the application of this concept currently carried out at the Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer" of the Helmholtz-Zentrum München and the LMU Munich is described. This review article strives for providing a compact overview on the state of the art of systems biology, its actual challenges, potential applications, chances and limitations in radiation oncology research working towards improved personalised therapy concepts using this relatively new methodology.
| S-EPMC3901372 | biostudies-literature
Project description:Motivation:Identification of novel therapeutic effects for existing US Food and Drug Administration (FDA)-approved drugs, drug repurposing, is an approach aimed to dramatically shorten the drug discovery process, which is costly, slow and risky. Several computational approaches use transcriptional data to find potential repurposing candidates. The main hypothesis of such approaches is that if gene expression signature of a particular drug is opposite to the gene expression signature of a disease, that drug may have a potential therapeutic effect on the disease. However, this may not be optimal since it fails to consider the different roles of genes and their dependencies at the system level. Results:We propose a systems biology approach to discover novel therapeutic roles for established drugs that addresses some of the issues in the current approaches. To do so, we use publicly available drug and disease data to build a drug-disease network by considering all interactions between drug targets and disease-related genes in the context of all known signaling pathways. This network is integrated with gene-expression measurements to identify drugs with new desired therapeutic effects based on a system-level analysis method. We compare the proposed approach with the drug repurposing approach proposed by Sirota et al. on four human diseases: idiopathic pulmonary fibrosis, non-small cell lung cancer, prostate cancer and breast cancer. We evaluate the proposed approach based on its ability to re-discover drugs that are already FDA-approved for a given disease. Availability and implementation:The R package DrugDiseaseNet is under review for publication in Bioconductor and is available at https://github.com/azampvd/DrugDiseaseNet. Supplementary information:Supplementary data are available at Bioinformatics online.
| S-EPMC6084573 | biostudies-literature
Project description:There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology (SCB) (Nat Chem Biol 3: 447-450, 2007).The overarching goal of computational SCB is to develop tools for integrated chemical-biological data acquisition, filtering and processing, by taking into account relevant information related to interactions between proteins and small molecules, possible metabolic transformations of small molecules, as well as associated information related to genes, networks, small molecules, and, where applicable, mutants and variants of those proteins. There is yet an unmet need to develop an integrated in silico pharmacology/systems biology continuum that embeds drug-target-clinical outcome (DTCO) triplets, a capability that is vital to the future of chemical biology, pharmacology, and systems biology. Through the development of the SCB approach, scientists will be able to start addressing, in an integrated simulation environment, questions that make the best use of our ever-growing chemical and biological data repositories at the system-wide level. This chapter reviews some of the major research concepts and describes key components that constitute the emerging area of computational systems chemical biology.
| S-EPMC3547368 | biostudies-literature
Project description:Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed clinical cancer research. They have revealed novel molecular markers of cancer subtypes, metastasis, and drug sensitivity and resistance. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and great volumes of data are accumulating at a rapid pace. Here we discuss these challenges, and show how integrative computational biology can help diminish them by creating new software tools, analytical methods, and data standards.
| S-EPMC3179275 | biostudies-literature
Project description:BackgroundPatients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19.ObjectivesTo explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied.MethodsAs a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis.ResultsWe found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising.ConclusionsPathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.
| S-EPMC7831776 | biostudies-literature
Project description:BackgroundPatients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19.ObjectivesTo explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied.MethodsAs a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis.ResultsWe found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising.ConclusionsPathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.
| S-EPMC7373141 | biostudies-literature
Project description:Gallbladder cancer (GBC) has a lower incidence rate among the population relative to other cancer types but is a major contributor to the total number of biliary tract system cancer cases. GBC is distinguished from other malignancies by its high mortality, marked geographical variation and poor prognosis. To date no systemic targeted therapy is available for GBC. The main objective of this study is to determine the molecular signatures correlated with GBC development using integrative systems level approaches. We performed analysis of publicly available transcriptomic data to identify differentially regulated genes and pathways. Differential co-expression network analysis and transcriptional regulatory network analysis was performed to identify hub genes and hub transcription factors (TFs) associated with GBC pathogenesis and progression. Subsequently, we assessed the epithelial-mesenchymal transition (EMT) status of the hub genes using a combination of three scoring methods. The identified hub genes including, CDC6, MAPK15, CCNB2, BIRC7, L3MBTL1 were found to be regulators of cell cycle components which suggested their potential role in GBC pathogenesis and progression.
| S-EPMC8397040 | biostudies-literature