Dataset Information

Inferring Drosophila gap gene regulatory network: a parameter sensitivity and perturbation analysis.

ABSTRACT: BACKGROUND: Inverse modelling of gene regulatory networks (GRNs) capable of simulating continuous spatio-temporal biological processes requires accurate data and a good description of the system. If quantitative relations between genes cannot be extracted from direct measurements, an efficient method to estimate the unknown parameters is mandatory. A model that has been proposed to simulate spatio-temporal gene expression patterns is the connectionist model. This method describes the quantitative dynamics of a regulatory network in space. The model parameters are estimated by means of model-fitting algorithms. The gene interactions are identified without making any prior assumptions concerning the network connectivity. As a result, the inverse modelling might lead to multiple circuits showing the same quantitative behaviour and it is not possible to identify one optimal circuit. Consequently, it is important to address the quality of the circuits in terms of model robustness. RESULTS: Here we investigate the sensitivity and robustness of circuits obtained from reverse engineering a model capable of simulating measured gene expression patterns. As a case study we use the early gap gene segmentation mechanism in Drosophila melanogaster. We consider the limitations of the connectionist model used to describe GRN Inferred from spatio-temporal gene expression. We address the problem of circuit discrimination, where the selection criterion within the optimization technique is based of the least square minimization on the error between data and simulated results. CONCLUSION: Parameter sensitivity analysis allows one to discriminate between circuits having significant parameter and qualitative differences but exhibiting the same quantitative pattern. Furthermore, we show that using a stochastic model derived from a deterministic solution, one can introduce fluctuations within the model to analyze the circuits' robustness. Ultimately, we show that there is a close relation between circuit sensitivity and robustness to fluctuation, and that circuit robustness is rather modular than global. The current study shows that reverse engineering of GRNs should not only focus on estimating parameters by minimizing the difference between observation and simulation but also on other model properties. Our study suggests that multi-objective optimization based on robustness and sensitivity analysis has to be considered.

SUBMITTER: Fomekong-Nanfack Y

PROVIDER: S-EPMC2761871 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Inferring Drosophila gap gene regulatory network: a parameter sensitivity and perturbation analysis.

Fomekong-Nanfack Yves Y Postma Marten M Kaandorp Jaap A JA

BMC systems biology 20090921

<h4>Background</h4>Inverse modelling of gene regulatory networks (GRNs) capable of simulating continuous spatio-temporal biological processes requires accurate data and a good description of the system. If quantitative relations between genes cannot be extracted from direct measurements, an efficient method to estimate the unknown parameters is mandatory. A model that has been proposed to simulate spatio-temporal gene expression patterns is the connectionist model. This method describes the quan ...[more]

PMID: 19769791

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Project description:BackgroundThe detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency.ResultsWe developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded.ConclusionsThe reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3) functional important sites are not exclusively located in cis-regulatory elements, but are rather dispersed through regulatory region. It is of importance that some of the sites with high functional impact in hb, Kr and kni regulatory regions coincide with strong sites annotated and verified in Dnase I footprint assays.

Project description:BACKGROUND:Although many of the genic features in Mycobacterium abscessus have been fully validated, a comprehensive understanding of the regulatory elements remains lacking. Moreover, there is little understanding of how the organism regulates its transcriptomic profile, enabling cells to survive in hostile environments. Here, to computationally infer the gene regulatory network for Mycobacterium abscessus we propose a novel statistical computational modelling approach: BayesIan gene regulatory Networks inferreD via gene coExpression and compaRative genomics (BINDER). In tandem with derived experimental coexpression data, the property of genomic conservation is exploited to probabilistically infer a gene regulatory network in Mycobacterium abscessus.Inference on regulatory interactions is conducted by combining 'primary' and 'auxiliary' data strata. The data forming the primary and auxiliary strata are derived from RNA-seq experiments and sequence information in the primary organism Mycobacterium abscessus as well as ChIP-seq data extracted from a related proxy organism Mycobacterium tuberculosis. The primary and auxiliary data are combined in a hierarchical Bayesian framework, informing the apposite bivariate likelihood function and prior distributions respectively. The inferred relationships provide insight to regulon groupings in Mycobacterium abscessus. RESULTS:We implement BINDER on data relating to a collection of 167,280 regulator-target pairs resulting in the identification of 54 regulator-target pairs, across 5 transcription factors, for which there is strong probability of regulatory interaction. CONCLUSIONS:The inferred regulatory interactions provide insight to, and a valuable resource for further studies of, transcriptional control in Mycobacterium abscessus, and in the family of Mycobacteriaceae more generally. Further, the developed BINDER framework has broad applicability, useable in settings where computational inference of a gene regulatory network requires integration of data sources derived from both the primary organism of interest and from related proxy organisms.

Project description:Recent breakthrough in spatial transcriptomics has brought great opportunities for exploring gene regulatory networks (GRNs) from a brand-new perspective. Especially, the local expression patterns and spatio-temporal regulation mechanisms captured by spatial expression images allow more delicate delineation of the interplay between transcript factors and their target genes. However, the complexity and size of spatial image collections pose significant challenges to GRN inference using image-based methods. Extracting regulatory information from expression images is difficult due to the lack of supervision and the multi-instance nature of the problem, where a gene often corresponds to multiple images captured from different views. While graph models, particularly graph neural networks, have emerged as a promising method for leveraging underlying structure information from known GRNs, incorporating expression images into graphs is not straightforward. To address these challenges, we propose a two-stage approach, MIGGRI, for capturing comprehensive regulatory patterns from image collections for each gene and known interactions. Our approach involves a multi-instance graph neural network (GNN) model for GRN inference, which first extracts gene regulatory features from spatial expression images via contrastive learning, and then feeds them to a multi-instance GNN for semi-supervised learning. We apply our approach to a large set of Drosophila embryonic spatial gene expression images. MIGGRI achieves outstanding performance in the inference of GRNs for early eye development and mesoderm development of Drosophila, and shows robustness in the scenarios of missing image information. Additionally, we perform interpretable analysis on image reconstruction and functional subgraphs that may reveal potential pathways or coordinate regulations. By leveraging the power of graph neural networks and the information contained in spatial expression images, our approach has the potential to advance our understanding of gene regulation in complex biological systems.

Dataset Information

Inferring Drosophila gap gene regulatory network: a parameter sensitivity and perturbation analysis.

Publications

Inferring Drosophila gap gene regulatory network: a parameter sensitivity and perturbation analysis.

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