Using a State-Space Model and Location Analysis to Infer Time-Delayed Regulatory Networks

Computational gene regulation models provide a means for scientists to draw biological inferences from time-course gene expression data. Based on the state-space approach, we developed a new modeling tool for inferring gene regulatory networks, called time-delayed Gene Regulatory Networks (tdGRNs). tdGRN takes time-delayed regulatory relationships into consideration when developing the model. In addition, a priori biological knowledge from genome-wide location analysis is incorporated into the structure of the gene regulatory network. tdGRN is evaluated on both an artificial dataset and a published gene expression data set. It not only determines regulatory relationships that are known to exist but also uncovers potential new ones. The results indicate that the proposed tool is effective in inferring gene regulatory relationships with time delay. tdGRN is complementary to existing methods for inferring gene regulatory networks. The novel part of the proposed tool is that it is able to infer time-delayed regulatory relationships.     

Gene expression network reconstruction by convex feature selection when incorporating genetic perturbations

Cellular gene expression measurements contain regulatory information that can be used to discover novel network relationships. Here, we present a new algorithm for network reconstruction powered by the adaptive lasso, a theoretically and empirically well-behaved method for selecting the regulatory features of a network. Any algorithms designed for network discovery that make use of directed probabilistic graphs require perturbations, produced by either experiments or naturally occurring genetic variation, to successfully infer unique regulatory relationships from gene expression data. Our approach makes use of appropriately selected cis-expression Quantitative Trait Loci (cis-eQTL), which provide a sufficient set of independent perturbations for maximum network resolution. We compare the performance of our network reconstruction algorithm to four other approaches: the PC-algorithm, QTLnet, the QDG algorithm, and the NEO algorithm, all of which have been used to reconstruct directed networks among phenotypes leveraging QTL. We show that the adaptive lasso can outperform these algorithms for networks of ten genes and ten cis-eQTL, and is competitive with the QDG algorithm for networks with thirty genes and thirty cis-eQTL, with rich topologies and hundreds of samples. Using this novel approach, we identify unique sets of directed relationships in Saccharomyces cerevisiae when analyzing genome-wide gene expression data for an intercross between a wild strain and a lab strain. We recover novel putative network relationships between a tyrosine biosynthesis gene (TYR1), and genes involved in endocytosis (RCY1), the spindle checkpoint (BUB2), sulfonate catabolism (JLP1), and cell-cell communication (PRM7). Our algorithm provides a synthesis of feature selection methods and graphical model theory that has the potential to reveal new directed regulatory relationships from the analysis of population level genetic and gene expression data.     

Functional genomics as an emerging strategy for the investigation of central mechanisms in experimental hypertension

Centrally mediated increases in sympathetic nerve activity and attenuated arterial baroreflexes contribute to the pathogenesis of hypertension. Despite the characterization of cellular and physiological mechanisms that regulate blood pressure and alterations that contribute to hypertension, the genetic and molecular basis of this pathophysiology remains poorly understood. Strategies to identify genes that contribute to central pathophysiologic mechanisms in hypertension include integrative biochemistry and physiology as well as functional genomics. This article summarizes recent progress in applying functional genomics to elucidate the genetic basis of altered central blood pressure regulatory mechanisms in hypertension. We describe approaches others and we have undertaken to investigate gene expression profiles in hypertensive models in order to identify genes that contribute to the pathogenesis of hypertension. Finally, we provide the readers a roadmap for negotiating the route from experimental findings of gene expression profiling to translating their therapeutic potential. The combination of gene expression profiling and the phenotypic characterization of in vitro and in vivo loss or gain of function experiments for candidate genes have the potential to identify genes involved in the pathogenesis of hypertension and may present novel targets for therapy.     

Estimating gene regulatory networks and protein-protein interactions of Saccharomyces cerevisiae from multiple genome-wide data

MOTIVATION: Biological processes in cells are properly performed by gene regulations, signal transductions and interactions between proteins. To understand such molecular networks, we propose a statistical method to estimate gene regulatory networks and protein-protein interaction networks simultaneously from DNA microarray data, protein-protein interaction data and other genome-wide data. RESULTS: We unify Bayesian networks and Markov networks for estimating gene regulatory networks and protein-protein interaction networks according to the reliability of each biological information source. Through the simultaneous construction of gene regulatory networks and protein-protein interaction networks of Saccharomyces cerevisiae cell cycle, we predict the role of several genes whose functions are currently unknown. By using our probabilistic model, we can detect false positives of high-throughput data, such as yeast two-hybrid data. In a genome-wide experiment, we find possible gene regulatory relationships and protein-protein interactions between large protein complexes that underlie complex regulatory mechanisms of biological processes.     

Modeling Genome-Wide Dynamic Regulatory Network in Mouse Lungs with Influenza Infection Using High-Dimensional Ordinary Differential Equations

The immune response to viral infection is regulated by an intricate network of many genes and their products. The reverse engineering of gene regulatory networks (GRNs) using mathematical models from time course gene expression data collected after influenza infection is key to our understanding of the mechanisms involved in controlling influenza infection within a host. A five-step pipeline: detection of temporally differentially expressed genes, clustering genes into co-expressed modules, identification of network structure, parameter estimate refinement, and functional enrichment analysis, is developed for reconstructing high-dimensional dynamic GRNs from genome-wide time course gene expression data. Applying the pipeline to the time course gene expression data from influenza-infected mouse lungs, we have identified 20 distinct temporal expression patterns in the differentially expressed genes and constructed a module-based dynamic network using a linear ODE model. Both intra-module and inter-module annotations and regulatory relationships of our inferred network show some interesting findings and are highly consistent with existing knowledge about the immune response in mice after influenza infection. The proposed method is a computationally efficient, data-driven pipeline bridging experimental data, mathematical modeling, and statistical analysis. The application to the influenza infection data elucidates the potentials of our pipeline in providing valuable insights into systematic modeling of complicated biological processes.     

Epigenomics of cancer – emerging new concepts

The complexity of the mammalian genome is regulated by heritable epigenetic mechanisms, which provide the basis for differentiation, development and cellular homeostasis. These mechanisms act on the level of chromatin, by modifying DNA, histone proteins and nucleosome density/composition. During the last decade it became clear that cancer is defined by a variety of epigenetic changes, which occur in early stages of disease and parallel genetic mutations. With the advent of new technologies we are just starting to unravel the cancer epigenome and latest mechanistic findings provide the first clue as to how altered epigenetic patterns might occur in different cancers. Here we review latest findings on chromatin related mechanisms and hypothesize how their impairment might contribute to the altered epigenome of cancer cells.     

Inferring the perturbed microRNA regulatory networks from gene expression data using a network propagation based method

Background

MicroRNAs (miRNAs) are a class of endogenous small regulatory RNAs. Identifications of the dys-regulated or perturbed miRNAs and their key target genes are important for understanding the regulatory networks associated with the studied cellular processes. Several computational methods have been developed to infer the perturbed miRNA regulatory networks by integrating genome-wide gene expression data and sequence-based miRNA-target predictions. However, most of them only use the expression information of the miRNA direct targets, rarely considering the secondary effects of miRNA perturbation on the global gene regulatory networks.

Results

We proposed a network propagation based method to infer the perturbed miRNAs and their key target genes by integrating gene expressions and global gene regulatory network information. The method used random walk with restart in gene regulatory networks to model the network effects of the miRNA perturbation. Then, it evaluated the significance of the correlation between the network effects of the miRNA perturbation and the gene differential expression levels with a forward searching strategy. Results show that our method outperformed several compared methods in rediscovering the experimentally perturbed miRNAs in cancer cell lines. Then, we applied it on a gene expression dataset of colorectal cancer clinical patient samples and inferred the perturbed miRNA regulatory networks of colorectal cancer, including several known oncogenic or tumor-suppressive miRNAs, such as miR-17, miR-26 and miR-145.

Conclusions

Our network propagation based method takes advantage of the network effect of the miRNA perturbation on its target genes. It is a useful approach to infer the perturbed miRNAs and their key target genes associated with the studied biological processes using gene expression data.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-255) contains supplementary material, which is available to authorized users.     

Identification of genetic networks

In this report, we propose the use of structural equations as a tool for identifying and modeling genetic networks and genetic algorithms for searching the most likely genetic networks that best fit the data. After genetic networks are identified, it is fundamental to identify those networks influencing cell phenotypes. To accomplish this task we extend the concept of differential expression of the genes, widely used in gene expression data analysis, to genetic networks. We propose a definition for the differential expression of a genetic network and use the generalized T2 statistic to measure the ability of genetic networks to distinguish different phenotypes. However, describing the differential expression of genetic networks is not enough for understanding biological systems because differences in the expression of genetic networks do not directly reflect regulatory strength between gene activities. Therefore, in this report we also introduce the concept of differentially regulated genetic networks, which has the potential to assess changes of gene regulation in response to perturbation in the environment and may provide new insights into the mechanism of diseases and biological processes. We propose five novel statistics to measure the differences in regulation of genetic networks. To illustrate the concepts and methods for reconstruction of genetic networks and identification of association of genetic networks with function, we applied the proposed models and algorithms to three data sets.     

工业微生物遗传和环境扰动的调控和适应进化

开发工业微生物,使其利用可再生的原料生产生物燃料、大宗化学品、食品添加剂和营养品、药物以及工业酶等,是发展生物产业的基础。工业微生物高产和胁迫抗性等鲁棒性状受复杂遗传调控网络控制,其改造需要从全基因组尺度进行系统的全局的多位点的扰动,以达到快速积累多样性基因型突变并产生所期望的表型。文中对工业微生物鲁棒性状的遗传调控与胁迫响应机制、基因组全局扰动与多位点快速进化以及细胞水平氧还平衡的全局扰动进行了简要综述,未来需要继续借助系统生物学和合成生物学手段,进一步加强对工业环境下工业微生物鲁棒性状调控机理的解析与建模预测以及系统的工程改造。     

Estimating the Stochastic Bifurcation Structure of Cellular Networks

High throughput measurement of gene expression at single-cell resolution, combined with systematic perturbation of environmental or cellular variables, provides information that can be used to generate novel insight into the properties of gene regulatory networks by linking cellular responses to external parameters. In dynamical systems theory, this information is the subject of bifurcation analysis, which establishes how system-level behaviour changes as a function of parameter values within a given deterministic mathematical model. Since cellular networks are inherently noisy, we generalize the traditional bifurcation diagram of deterministic systems theory to stochastic dynamical systems. We demonstrate how statistical methods for density estimation, in particular, mixture density and conditional mixture density estimators, can be employed to establish empirical bifurcation diagrams describing the bistable genetic switch network controlling galactose utilization in yeast Saccharomyces cerevisiae. These approaches allow us to make novel qualitative and quantitative observations about the switching behavior of the galactose network, and provide a framework that might be useful to extract information needed for the development of quantitative network models.     

Towards model-driven characterization and manipulation of plant lipid metabolism

Plant lipids have versatile applications and provide essential fatty acids in human diet. Therefore, there has been a growing interest to better characterize the genetic basis, regulatory networks, and metabolic pathways that shape lipid quantity and composition. Addressing these issues is challenging due to context-specificity of lipid metabolism integrating environmental, developmental, and tissue-specific cues. Here we systematically review the known metabolic pathways and regulatory interactions that modulate the levels of storage lipids in oilseeds. We argue that the current understanding of lipid metabolism provides the basis for its study in the context of genome-wide plant metabolic networks with the help of approaches from constraint-based modeling and metabolic flux analysis. The focus is on providing a comprehensive summary of the state-of-the-art of modeling plant lipid metabolic pathways, which we then contrast with the existing modeling efforts in yeast and microalgae. We then point out the gaps in knowledge of lipid metabolism, and enumerate the recent advances of using genome-wide association and quantitative trait loci mapping studies to unravel the genetic regulations of lipid metabolism. Finally, we offer a perspective on how advances in the constraint-based modeling framework can propel further characterization of plant lipid metabolism and its rational manipulation.