Dataset Information

Coordinating Role of RXR? in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

ABSTRACT: During various inflammatory processes circulating cytokines including IL-6, IL-1?, and TNF? elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXR? playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXR? gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXR? functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.

SUBMITTER: Keller R

PROVIDER: S-EPMC4699813 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

Keller Roland R Klein Marcus M Thomas Maria M Dräger Andreas A Metzger Ute U Templin Markus F MF Joos Thomas O TO Thasler Wolfgang E WE Zell Andreas A Zanger Ulrich M UM

PLoS computational biology 20160104 1

During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses ...[more]

PMID: 26727233

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Project description:BackgroundTo date, only a limited number of transcriptional regulatory interactions have been uncovered. In a pilot study integrating sequence data with microarray data, a position weight matrix (PWM) performed poorly in inferring transcriptional interactions (TIs), which represent physical interactions between transcription factors (TF) and upstream sequences of target genes. Inferring a TI means that the promoter sequence of a target is inferred to match the consensus sequence motifs of a potential TF, and their interaction type such as AT or RT is also predicted. Thus, a robust PWM (rPWM) was developed to search for consensus sequence motifs. In addition to rPWM, one feature extracted from ChIP-chip data was incorporated to identify potential TIs under specific conditions. An interaction type classifier was assembled to predict activation/repression of potential TIs using microarray data. This approach, combining an adaptive (learning) fuzzy inference system and an interaction type classifier to predict transcriptional regulatory networks, was named AdaFuzzy.ResultsAdaFuzzy was applied to predict TIs using real genomics data from Saccharomyces cerevisiae. Following one of the latest advances in predicting TIs, constrained probabilistic sparse matrix factorization (cPSMF), and using 19 transcription factors (TFs), we compared AdaFuzzy to four well-known approaches using over-representation analysis and gene set enrichment analysis. AdaFuzzy outperformed these four algorithms. Furthermore, AdaFuzzy was shown to perform comparably to 'ChIP-experimental method' in inferring TIs identified by two sets of large scale ChIP-chip data, respectively. AdaFuzzy was also able to classify all predicted TIs into one or more of the four promoter architectures. The results coincided with known promoter architectures in yeast and provided insights into transcriptional regulatory mechanisms.ConclusionAdaFuzzy successfully integrates multiple types of data (sequence, ChIP, and microarray) to predict transcriptional regulatory networks. The validated success in the prediction results implies that AdaFuzzy can be applied to uncover TIs in yeast.

Project description:Anion and cation sensing aspects of a terpyridyl-imidazole based receptor have been utilized in this work for the fabrication of multiply configurable Boolean and fuzzy logic systems. The terpyridine moiety of the receptor is used for cation sensing through coordination, whereas the imidazole motif is utilized for anion sensing via hydrogen bonding interaction and/or anion-induced deprotonation, and the recognition event was monitored through absorption and emission spectroscopy. The receptor functions as a selective sensor for F- and Fe2+ among the studied anions and cations, respectively. Interestingly, the complexation of the receptor by Fe2+ and its decomplexation by F- and deprotonation of the receptor by F- and restoration to its initial form by acid are reversible and can be recycled. The receptor can mimic various logic operations such as combinatorial logic gate and keypad lock using its spectral responses through the sequential use of ionic inputs. Conducting very detailed sensing studies by varying the concentration of the analytes within a wide domain is often very time-consuming, laborious, and expensive. To decrease the time and expenses of the investigations, soft computing approaches such as artificial neural networks (ANNs), fuzzy logic, or adaptive neuro-fuzzy inference system (ANFIS) can be recommended to predict the experimental spectral data. Soft computing approaches to artificial intelligence (AI) include neural networks, fuzzy systems, evolutionary computation, and other tools based on statistical and mathematical optimizations. This study compares fuzzy, ANN, and ANFIS outputs to model the protonation-deprotonation and complexation-decomplexation behaviors of the receptor. Triangular membership functions (trimf) are used to model the ANFIS methodology. A good correlation is observed between experimental and model output data. The testing root mean square error (RMSE) for the ANFIS model is 0.0023 for protonation-deprotonation and 0.0036 for complexation-decomplexation data.

Dataset Information

Coordinating Role of RXR? in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

Publications

Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

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