Bayesian non-negative factor analysis for reconstructing transcription factor mediated regulatory networks

<p>Abstract</p> <p>Background</p> <p>Transcriptional regulation by transcription factor (TF) controls the time and abundance of mRNA transcription. Due to the limitation of current proteomics technologies, large scale measurements of protein level activities of TFs is usually infeasible, making computational reconstruction of transcriptional regulatory network a difficult task.</p> <p>Results</p> <p>We proposed here a novel Bayesian non-negative factor model for TF mediated regulatory networks. Particularly, the non-negative TF activities and sample clustering effect are modeled as the factors from a Dirichlet process mixture of rectified Gaussian distributions, and the sparse regulatory coefficients are modeled as the loadings from a sparse distribution that constrains its sparsity using knowledge from database; meantime, a Gibbs sampling solution was developed to infer the underlying network structure and the unknown TF activities simultaneously. The developed approach has been applied to simulated system and breast cancer gene expression data. Result shows that, the proposed method was able to systematically uncover TF mediated transcriptional regulatory network structure, the regulatory coefficients, the TF protein level activities and the sample clustering effect. The regulation target prediction result is highly coordinated with the prior knowledge, and sample clustering result shows superior performance over previous molecular based clustering method.</p> <p>Conclusions</p> <p>The results demonstrated the validity and effectiveness of the proposed approach in reconstructing transcriptional networks mediated by TFs through simulated systems and real data.</p

Identifying targets of multiple co-regulating transcription factors from expression time-series by Bayesian model comparison

Background: Complete transcriptional regulatory network inference is a huge challenge because of the complexity of the network and sparsity of available data. One approach to make it more manageable is to focus on the inference of context-specific networks involving a few interacting transcription factors (TFs) and all of their target genes. Results: We present a computational framework for Bayesian statistical inference of target genes of multiple interacting TFs from high-throughput gene expression time-series data. We use ordinary differential equation models that describe transcription of target genes taking into account combinatorial regulation. The method consists of a training and a prediction phase. During the training phase we infer the unobserved TF protein concentrations on a subnetwork of approximately known regulatory structure. During the prediction phase we apply Bayesian model selection on a genome-wide scale and score all alternative regulatory structures for each target gene. We use our methodology to identify targets of five TFs regulating Drosophila melanogaster mesoderm development. We find that confident predicted links between TFs and targets are significantly enriched for supporting ChIP-chip binding events and annotated TF-gene interations. Our method statistically significantly outperforms existing alternatives. Conclusions: Our results show that it is possible to infer regulatory links between multiple interacting TFs and their target genes even from a single relatively short time series and in presence of unmodelled confounders and unreliable prior knowledge on training network connectivity. Introducing data from several different experimental perturbations significantly increases the accuracy

Beyond element-wise interactions: identifying complex interactions in biological processes

Background: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call “complex” these types of interaction and propose ways to identify them from time-series observations. Methodology: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. Conclusions: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem

New insights into the genetic control of gene expression using a Bayesian multi-tissue approach.

The majority of expression quantitative trait locus (eQTL) studies have been carried out in single tissues or cell types, using methods that ignore information shared across tissues. Although global analysis of RNA expression in multiple tissues is now feasible, few integrated statistical frameworks for joint analysis of gene expression across tissues combined with simultaneous analysis of multiple genetic variants have been developed to date. Here, we propose Sparse Bayesian Regression models for mapping eQTLs within individual tissues and simultaneously across tissues. Testing these on a set of 2,000 genes in four tissues, we demonstrate that our methods are more powerful than traditional approaches in revealing the true complexity of the eQTL landscape at the systems-level. Highlighting the power of our method, we identified a two-eQTL model (cis/trans) for the Hopx gene that was experimentally validated and was not detected by conventional approaches. We showed common genetic regulation of gene expression across four tissues for ∼27% of transcripts, providing >5 fold increase in eQTLs detection when compared with single tissue analyses at 5% FDR level. These findings provide a new opportunity to uncover complex genetic regulatory mechanisms controlling global gene expression while the generality of our modelling approach makes it adaptable to other model systems and humans, with broad application to analysis of multiple intermediate and whole-body phenotypes

Statistical Methods in Integrative Genomics

Statistical methods in integrative genomics aim to answer important biology questions by jointly analyzing multiple types of genomic data (vertical integration) or aggregating the same type of data across multiple studies (horizontal integration). In this article, we introduce different types of genomic data and data resources, and then review statistical methods of integrative genomics, with emphasis on the motivation and rationale of these methods. We conclude with some summary points and future research directions

Overlapping stochastic block models with application to the French political blogosphere

Complex systems in nature and in society are often represented as networks, describing the rich set of interactions between objects of interest. Many deterministic and probabilistic clustering methods have been developed to analyze such structures. Given a network, almost all of them partition the vertices into disjoint clusters, according to their connection profile. However, recent studies have shown that these techniques were too restrictive and that most of the existing networks contained overlapping clusters. To tackle this issue, we present in this paper the Overlapping Stochastic Block Model. Our approach allows the vertices to belong to multiple clusters, and, to some extent, generalizes the well-known Stochastic Block Model [Nowicki and Snijders (2001)]. We show that the model is generically identifiable within classes of equivalence and we propose an approximate inference procedure, based on global and local variational techniques. Using toy data sets as well as the French Political Blogosphere network and the transcriptional network of Saccharomyces cerevisiae, we compare our work with other approaches.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS382 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

New components of the Dictyostelium PKA pathway revealed by Bayesian analysis of expression data

<p>Abstract</p> <p>Background</p> <p>Identifying candidate genes in genetic networks is important for understanding regulation and biological function. Large gene expression datasets contain relevant information about genetic networks, but mining the data is not a trivial task. Algorithms that infer Bayesian networks from expression data are powerful tools for learning complex genetic networks, since they can incorporate prior knowledge and uncover higher-order dependencies among genes. However, these algorithms are computationally demanding, so novel techniques that allow targeted exploration for discovering new members of known pathways are essential.</p> <p>Results</p> <p>Here we describe a Bayesian network approach that addresses a specific network within a large dataset to discover new components. Our algorithm draws individual genes from a large gene-expression repository, and ranks them as potential members of a known pathway. We apply this method to discover new components of the cAMP-dependent protein kinase (PKA) pathway, a central regulator of <it>Dictyostelium discoideum </it>development. The PKA network is well studied in <it>D. discoideum </it>but the transcriptional networks that regulate PKA activity and the transcriptional outcomes of PKA function are largely unknown. Most of the genes highly ranked by our method encode either known components of the PKA pathway or are good candidates. We tested 5 uncharacterized highly ranked genes by creating mutant strains and identified a candidate cAMP-response element-binding protein, yet undiscovered in <it>D. discoideum</it>, and a histidine kinase, a candidate upstream regulator of PKA activity.</p> <p>Conclusions</p> <p>The single-gene expansion method is useful in identifying new components of known pathways. The method takes advantage of the Bayesian framework to incorporate prior biological knowledge and discovers higher-order dependencies among genes while greatly reducing the computational resources required to process high-throughput datasets.</p

Integrative modeling of transcriptional regulation in response to antirheumatic therapy

<p>Abstract</p> <p>Background</p> <p>The investigation of gene regulatory networks is an important issue in molecular systems biology and significant progress has been made by combining different types of biological data. The purpose of this study was to characterize the transcriptional program induced by etanercept therapy in patients with rheumatoid arthritis (RA). Etanercept is known to reduce disease symptoms and progression in RA, but the underlying molecular mechanisms have not been fully elucidated.</p> <p>Results</p> <p>Using a DNA microarray dataset providing genome-wide expression profiles of 19 RA patients within the first week of therapy we identified significant transcriptional changes in 83 genes. Most of these genes are known to control the human body's immune response. A novel algorithm called TILAR was then applied to construct a linear network model of the genes' regulatory interactions. The inference method derives a model from the data based on the Least Angle Regression while incorporating DNA-binding site information. As a result we obtained a scale-free network that exhibits a self-regulating and highly parallel architecture, and reflects the pleiotropic immunological role of the therapeutic target TNF-alpha. Moreover, we could show that our integrative modeling strategy performs much better than algorithms using gene expression data alone.</p> <p>Conclusion</p> <p>We present TILAR, a method to deduce gene regulatory interactions from gene expression data by integrating information on transcription factor binding sites. The inferred network uncovers gene regulatory effects in response to etanercept and thus provides useful hypotheses about the drug's mechanisms of action.</p