Inferring Regulatory Networks by Combining Perturbation Screens and Steady State Gene Expression Profiles

Reconstructing transcriptional regulatory networks is an important task in functional genomics. Data obtained from experiments that perturb genes by knockouts or RNA interference contain useful information for addressing this reconstruction problem. However, such data can be limited in size and/or are expensive to acquire. On the other hand, observational data of the organism in steady state (e.g. wild-type) are more readily available, but their informational content is inadequate for the task at hand. We develop a computational approach to appropriately utilize both data sources for estimating a regulatory network. The proposed approach is based on a three-step algorithm to estimate the underlying directed but cyclic network, that uses as input both perturbation screens and steady state gene expression data. In the first step, the algorithm determines causal orderings of the genes that are consistent with the perturbation data, by combining an exhaustive search method with a fast heuristic that in turn couples a Monte Carlo technique with a fast search algorithm. In the second step, for each obtained causal ordering, a regulatory network is estimated using a penalized likelihood based method, while in the third step a consensus network is constructed from the highest scored ones. Extensive computational experiments show that the algorithm performs well in reconstructing the underlying network and clearly outperforms competing approaches that rely only on a single data source. Further, it is established that the algorithm produces a consistent estimate of the regulatory network.Comment: 24 pages, 4 figures, 6 table

Using temporal correlation in factor analysis for reconstructing transcription factor activities

Two-level gene regulatory networks consist of the transcription factors (TFs) in the top level and their regulated genes in the second level. The expression profiles of the regulated genes are the observed high-throughput data given by experiments such as microarrays. The activity profiles of the TFs are treated as hidden variables as well as the connectivity matrix that indicates the regulatory relationships of TFs with their regulated genes. Factor analysis (FA) as well as other methods, such as the network component algorithm, has been suggested for reconstructing gene regulatory networks and also for predicting TF activities. They have been applied to E. coli and yeast data with the assumption that these datasets consist of identical and independently distributed samples. Thus, the main drawback of these algorithms is that they ignore any time correlation existing within the TF profiles. In this paper, we extend previously studied FA algorithms to include time correlation within the transcription factors. At the same time, we consider connectivity matrices that are sparse in order to capture the existing sparsity present in gene regulatory networks. The TFs activity profiles obtained by this approach are significantly smoother than profiles from previous FA algorithms. The periodicities in profiles from yeast expression data become prominent in our reconstruction. Moreover, the strength of the correlation between time points is estimated and can be used to assess the suitability of the experimental time interval

Estimating sample-specific regulatory networks

Biological systems are driven by intricate interactions among the complex array of molecules that comprise the cell. Many methods have been developed to reconstruct network models of those interactions. These methods often draw on large numbers of samples with measured gene expression profiles to infer connections between genes (or gene products). The result is an aggregate network model representing a single estimate for the likelihood of each interaction, or "edge," in the network. While informative, aggregate models fail to capture the heterogeneity that is represented in any population. Here we propose a method to reverse engineer sample-specific networks from aggregate network models. We demonstrate the accuracy and applicability of our approach in several data sets, including simulated data, microarray expression data from synchronized yeast cells, and RNA-seq data collected from human lymphoblastoid cell lines. We show that these sample-specific networks can be used to study changes in network topology across time and to characterize shifts in gene regulation that may not be apparent in expression data. We believe the ability to generate sample-specific networks will greatly facilitate the application of network methods to the increasingly large, complex, and heterogeneous multi-omic data sets that are currently being generated, and ultimately support the emerging field of precision network medicine

Dynamic Bayesian networks in molecular plant science: inferring gene regulatory networks from multiple gene expression time series

To understand the processes of growth and biomass production in plants, we ultimately need to elucidate the structure of the underlying regulatory networks at the molecular level. The advent of high-throughput postgenomic technologies has spurred substantial interest in reverse engineering these networks from data, and several techniques from machine learning and multivariate statistics have recently been proposed. The present article discusses the problem of inferring gene regulatory networks from gene expression time series, and we focus our exposition on the methodology of Bayesian networks. We describe dynamic Bayesian networks and explain their advantages over other statistical methods. We introduce a novel information sharing scheme, which allows us to infer gene regulatory networks from multiple sources of gene expression data more accurately. We illustrate and test this method on a set of synthetic data, using three different measures to quantify the network reconstruction accuracy. The main application of our method is related to the problem of circadian regulation in plants, where we aim to reconstruct the regulatory networks of nine circadian genes in Arabidopsis thaliana from four gene expression time series obtained under different experimental conditions

A Posterior Probability Approach for Gene Regulatory Network Inference in Genetic Perturbation Data

Inferring gene regulatory networks is an important problem in systems biology. However, these networks can be hard to infer from experimental data because of the inherent variability in biological data as well as the large number of genes involved. We propose a fast, simple method for inferring regulatory relationships between genes from knockdown experiments in the NIH LINCS dataset by calculating posterior probabilities, incorporating prior information. We show that the method is able to find previously identified edges from TRANSFAC and JASPAR and discuss the merits and limitations of this approach

Inferring a Transcriptional Regulatory Network from Gene Expression Data Using Nonlinear Manifold Embedding

Transcriptional networks consist of multiple regulatory layers corresponding to the activity of global regulators, specialized repressors and activators of transcription as well as proteins and enzymes shaping the DNA template. Such intrinsic multi-dimensionality makes uncovering connectivity patterns difficult and unreliable and it calls for adoption of methodologies commensurate with the underlying organization of the data source. Here we present a new computational method that predicts interactions between transcription factors and target genes using a compendium of microarray gene expression data and the knowledge of known interactions between genes and transcription factors. The proposed method called Kernel Embedding of REgulatory Networks (KEREN) is based on the concept of gene-regulon association and it captures hidden geometric patterns of the network via manifold embedding. We applied KEREN to reconstruct gene regulatory interactions in the model bacteria E.coli on a genome-wide scale. Our method not only yields accurate prediction of verifiable interactions, which outperforms on certain metrics comparable methodologies, but also demonstrates the utility of a geometric approach to the analysis of high-dimensional biological data. We also describe the general application of kernel embedding techniques to some other function and network discovery algorithms

Inference of the genetic network regulating lateral root initiation in Arabidopsis thaliana

Regulation of gene expression is crucial for organism growth, and it is one of the challenges in Systems Biology to reconstruct the underlying regulatory biological networks from transcriptomic data. The formation of lateral roots in Arabidopsis thaliana is stimulated by a cascade of regulators of which only the interactions of its initial elements have been identified. Using simulated gene expression data with known network topology, we compare the performance of inference algorithms, based on different approaches, for which ready-to-use software is available. We show that their performance improves with the network size and the inclusion of mutants. We then analyse two sets of genes, whose activity is likely to be relevant to lateral root initiation in Arabidopsis, by integrating sequence analysis with the intersection of the results of the best performing methods on time series and mutants to infer their regulatory network. The methods applied capture known interactions between genes that are candidate regulators at early stages of development. The network inferred from genes significantly expressed during lateral root formation exhibits distinct scale-free, small world and hierarchical properties and the nodes with a high out-degree may warrant further investigation