Identification of responsive gene modules by network-based gene clustering and extending: application to inflammation and angiogenesis

Background  

Cell responses to environmental stimuli are usually organized as relatively separate responsive gene modules at the molecular level. Identification of responsive gene modules rather than individual differentially expressed (DE) genes will provide important information about the underlying molecular mechanisms. Most of current methods formulate module identification as an optimization problem: find the active sub-networks in the genome-wide gene network by maximizing the objective function considering the gene differential expression and/or the gene-gene co-expression information. Here we presented a new formulation of this task: a group of closely-connected and co-expressed DE genes in the gene network are regarded as the signatures of the underlying responsive gene modules; the modules can be identified by finding the signatures and then recovering the "missing parts" by adding the intermediate genes that connect the DE genes in the gene network.     

BinTree seeking: a novel approach to mine both bi-sparse and cohesive modules in protein interaction networks

Modern science of networks has brought significant advances to our understanding of complex systems biology. As a representative model of systems biology, Protein Interaction Networks (PINs) are characterized by a remarkable modular structures, reflecting functional associations between their components. Many methods were proposed to capture cohesive modules so that there is a higher density of edges within modules than those across them. Recent studies reveal that cohesively interacting modules of proteins is not a universal organizing principle in PINs, which has opened up new avenues for revisiting functional modules in PINs. In this paper, functional clusters in PINs are found to be able to form unorthodox structures defined as bi-sparse module. In contrast to the traditional cohesive module, the nodes in the bi-sparse module are sparsely connected internally and densely connected with other bi-sparse or cohesive modules. We present a novel protocol called the BinTree Seeking (BTS) for mining both bi-sparse and cohesive modules in PINs based on Edge Density of Module (EDM) and matrix theory. BTS detects modules by depicting links and nodes rather than nodes alone and its derivation procedure is totally performed on adjacency matrix of networks. The number of modules in a PIN can be automatically determined in the proposed BTS approach. BTS is tested on three real PINs and the results demonstrate that functional modules in PINs are not dominantly cohesive but can be sparse. BTS software and the supporting information are available at: www.csbio.sjtu.edu.cn/bioinf/BTS/.     

基于大脑皮层信息传输的脑电信息图示方法

提出一种基于大脑皮层信息传输的脑电地形图示方法—脑电信息图（Ｂｒａｉｎ ＩｎｆｏｒｍａｔｉｏｎＭａｐｐｉｎｇ － ＢＩＭ） 。其原理是从不同导联电极上采集脑电信号经相空间重建构成头皮电位信息传输矩阵, 将各导联信息传输时间序列的信息传输量和复杂度数据绘制成头皮拓扑分布图, 以直观地反映脑电信息传输分布模式在不同时相中的变化进程。该方法不仅是从新的角度观察大脑功能变化, 而且可克服传统的脑电频谱分段地形图不能表达长程脑电模式变化的不足。对局限性癫痫病患者的试用表明,脑电信息图能较好地反映癫痫发作前后的信息传输动向和复杂度（Ｋｃ 、Ｃ１ 、Ｃ２） 的变化趋势。结果提示,脑电信息图（ＢＩＭ） 有可能成为一种新的观察大脑功能活动的图示诊断方法,值得进一步深入研究。     

Identifying responsive functional modules from protein-protein interaction network

Proteins interact with each other within a cell, and those interactions give rise to the biological function and dynamical behavior of cellular systems. Generally, the protein interactions are temporal, spatial, or condition dependent in a specific cell, where only a small part of interactions usually take place under certain conditions. Recently, although a large amount of protein interaction data have been collected by high-throughput technologies, the interactions are recorded or summarized under various or different conditions and therefore cannot be directly used to identify signaling pathways or active networks, which are believed to work in specific cells under specific conditions. However, protein interactions activated under specific conditions may give hints to the biological process underlying corresponding phenotypes. In particular, responsive functional modules consist of protein interactions activated under specific conditions can provide insight into the mechanism underlying biological systems, e.g. protein interaction subnetworks found for certain diseases rather than normal conditions may help to discover potential biomarkers. From computational viewpoint, identifying responsive functional modules can be formulated as an optimization problem. Therefore, efficient computational methods for extracting responsive functional modules are strongly demanded due to the NP-hard nature of such a combinatorial problem. In this review, we first report recent advances in development of computational methods for extracting responsive functional modules or active pathways from protein interaction network and microarray data. Then from computational aspect, we discuss remaining obstacles and perspectives for this attractive and challenging topic in the area of systems biology.     

Modularity in vertebrate brain development and evolution.

Embryonic modularity and functional modularity are two principles of brain organization. Embryonic modules are histogenetic fields that are specified by position-dependent expression of patterning genes. Within each embryonic module, secondary and higher-level pattern formation takes places during development, finally giving rise to brain nuclei and cortical layers. Defined subsets of these structures become connected by fiber tracts to form the information-processing neural circuits, which represent the functional modules of the brain. We review evidence that a group of cell adhesion molecules, the cadherins, provides an adhesive code for both types of modularity, based on a preferentially homotypic binding mechanism. Embryonic modularity is transformed into functional modularity, in part by translating early-generated positional information into an array of adhesive cues, which regulate the binding of functional neural structures distributed across the embryonic modules. Brain modularity may provide a basis for adaptability in evolution.     

Genetic approach to neuroethology

In neuroethology, the nervous system and behavior are analyzed in the context of the animal's natural habitat and evolutionary history. For the last 30 years the influence of genetics on neuroethology has steadily grown, particularly in Drosophila. Genetic variants reveal new properties of neurons; they help to dissect neuronal circuits and complex behavioral systems; genetics provides new methods to visualize certain brain structures and to assign behavioral functions to them; and, finally, genetic variants can be used to test ecological models. While single-gene mutations can have highly specific behavioral effects, molecular analysis of the corresponding genes reveals that the latter normally have a much broader functional scope. The ‘graininess’ of a functional model of the brain, therefore, is defined by the independent regulatory units of the genes rather than by the genes themselves.     

Systematic identification of common functional modules related to heart failure with different etiologies

The development of heart failure (HF) is a complex process that can be initiated by multiple etiologies. Identifying common functional modules associated with HF is a challenging task. Here, we developed a systems method to identify these common functional modules by integrating multiple expression profiles, protein interactions from four species, gene function annotations, and text information. We identified 1439 consistently differentially expressed genes (CDEGs) across HF with different etiologies by applying three meta-analysis methods to multiple HF-related expression profiles. Using a weighted human interaction network constructed by combining interaction data from multiple species, we extracted 60 candidate CDEG modules. We further evaluated the functional relevance of each module by using expression, interaction network, functional annotations, and text information together. Finally, five functional modules with significant biological relevance were identified. We found that almost half of the genes in these modules are hubs in the weighted network, and that these modules can accurately classify HF patients from healthy subjects. We also identified many significantly enriched biological processes that contribute to the pathophysiology of HF, including two new ones, RNA splicing and vesicle-mediated protein transport. In summary, we proposed a novel framework to analyze common functional modules related to HF with different etiologies. Our findings provide important insights into the complex mechanism of HF. Further biological experimentations should be required to validate these novel biological processes.     

Encoding brain network response to free viewing of videos

A challenging goal for cognitive neuroscience researchers is to determine how mental representations are mapped onto the patterns of neural activity. To address this problem, functional magnetic resonance imaging (fMRI) researchers have developed a large number of encoding and decoding methods. However, previous studies typically used rather limited stimuli representation, like semantic labels and Wavelet Gabor filters, and largely focused on voxel-based brain patterns. Here, we present a new fMRI encoding model to predict the human brain’s responses to free viewing of video clips which aims to deal with this limitation. In this model, we represent the stimuli using a variety of representative visual features in the computer vision community, which can describe the global color distribution, local shape and spatial information and motion information contained in videos, and apply the functional connectivity to model the brain’s activity pattern evoked by these video clips. Our experimental results demonstrate that brain network responses during free viewing of videos can be robustly and accurately predicted across subjects by using visual features. Our study suggests the feasibility of exploring cognitive neuroscience studies by computational image/video analysis and provides a novel concept of using the brain encoding as a test-bed for evaluating visual feature extraction.     

Cohesive versus Flexible Evolution of Functional Modules in Eukaryotes

Although functionally related proteins can be reliably predicted from phylogenetic profiles, many functional modules do not seem to evolve cohesively according to case studies and systematic analyses in prokaryotes. In this study we quantify the extent of evolutionary cohesiveness of functional modules in eukaryotes and probe the biological and methodological factors influencing our estimates. We have collected various datasets of protein complexes and pathways in Saccheromyces cerevisiae. We define orthologous groups on 34 eukaryotic genomes and measure the extent of cohesive evolution of sets of orthologous groups of which members constitute a known complex or pathway. Within this framework it appears that most functional modules evolve flexibly rather than cohesively. Even after correcting for uncertain module definitions and potentially problematic orthologous groups, only 46% of pathways and complexes evolve more cohesively than random modules. This flexibility seems partly coupled to the nature of the functional module because biochemical pathways are generally more cohesively evolving than complexes.     

The Role of the Neuronal Network in Functional Evolution of the Mammalian Telencephalon

During evolution of the vertebrate telencephalon the analyzing-synthesizing function was divided between two structures: the screen one, optimal for mechanisms of discrete analysis of information, and the neuronal network, in which cortical, functionally specialized modules can create the generalized equivalent of their activity. In the screen and reticular structures, each of these mechanisms got a possibility of developing independently without restricting functional capabilities of the other one. This resulted in formation of two telencephalon structures developing in parallel and functionally related, the cortex and the neostriatum. Experimental data indicate that the neuronal network of neostriatum is a field for interaction of corticofugal signals. These signals form neuronal mosaics reflecting the dynamics of cortical activity as combination patterns. Thereby, in neostriatum, corticofugal signals spread over a large surface of the cortex are transformed into their three-dimensional equivalent similar to population coding of information that takes place in the brain sensory structures. The established system of interrelationships between the cortex and the neostriatum turned out to be rather universal and economic. As a result, a broad spectrum of functional brain capabilities that we can see in various representatives of mammals was formed during a relatively short time with the minimum of structural changes, mainly quantitative in character.     

ModuleSearch: finding functional modules in a protein-protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein-protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein-protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.     

Mining functional gene modules linked with rheumatoid arthritis using a SNP-SNP network

The identification of functional gene modules that are derived from integration of information from different types of networks is a powerful strategy for interpreting the etiology of complex diseases such as rheumatoid arthritis (RA). Genetic variants are known to increase the risk of developing RA. Here, a novel method, the construction of a genetic network, was used to mine functional gene modules linked with RA. A polymorphism interaction analy-sis (PIA) algorithm was used to obtain cooperating single nucleotide polymorphisms (SNPs) that contribute to RA disease. The acquired SNP pairs were used to construct a SNP-SNP network. Sub-networks defined by hub SNPs were then extracted and turned into gene modules by mapping SNPs to genes using dbSNP database. We per-formed Gene Ontology (GO) analysis on each gene module, and some GO terms enriched in the gene modules can be used to investigate clustered gene function for better understanding RA pathogenesis. This method was applied to the Genetic Analysis Workshop 15 (GAW 15) RA dataset. The results show that genes involved in func-tional gene modules, such as CD160 (rs744877) and RUNX1 (rs2051179), are especially relevant to RA, which is supported by previous reports. Furthermore, the 43 SNPs involved in the identified gene modules were found to be the best classifiers when used as variables for sample classification.     

Synthetic biology of minimal systems

“Synthetic biology” is a concept that has developed together with, or slightly after, “systems biology”. But while systems biology aims at the full understanding of large systems by integrating more and more details into their models, synthetic biology phrases different questions, namely: what particular biological function could be obtained with a certain known subsystem of reduced complexity; can this function be manipulated or engineered in artificial environments or genetically modified organisms; and if so, how? The most prominent representation of synthetic biology has so far been microbial engineering by recombinant DNA technology, employing modular concepts known from information technology. However, there are an increasing number of biophysical groups who follow similar strategies of dissecting cellular processes and networks, trying to identify functional minimal modules that could then be combined in a bottom-up approach towards biology. These modules are so far not as particularly defined by their impact on DNA processing, but rather influenced by core fields of biophysics, such as cell mechanics and membrane dynamics. This review will give an overview of some classical and some quite new biophysical strategies for constructing minimal systems of certain cellular modules. We will show that with recent advances in understanding of cytoskeletal and membrane elements, the time might have come to experimentally challenge the concept of a minimal cell.     

PTB or not to be: promiscuous, tolerant and Bizarro domains come of age

PTB domains are protein modules that usually interact with the cytoplasmic tail of a wide variety of growth factor receptors. In so doing, they mediate the transduction of extracellular information to specific downstream targets within the cell that ultimately determine the fate of a number of important biological processes such as cell growth and differentiation, cell cycle regulation and apoptosis. Recent structural and functional studies of PTB domains from a variety of cellular proteins have begun to shed light on the molecular mechanisms of action of these important protein modules. In the present review, we provide an account of such studies and suggest that PTB domains can be subdivided into three distinct categories on the basis of their topological differences. We also discuss the various mechanisms employed by the PTB domains in recognition of a diverse set of ligands without a consensus sequence. Finally, we discuss the role of molecular plasticity as a possible determinant of functional versatility of PTB domains.     

Dynamical correlation patterns and corresponding community structure in neural spontaneous activity at criticality

It has been considered that the state in the vicinity of a critical point, which is the point between ordered and disordered states, can underlie and facilitate information processing of the brain in various aspects. In this research, we numerically study the influence of criticality on one aspect of brain information processing, i.e., the community structure, which is an important characteristic of complex networks. We examine community structure of the functional connectivity in simulated brain spontaneous activity, which is based on dynamical correlations between neural activity patterns at different positions. The brain spontaneous activity is simulated by a neural field model whose parameter covers subcritical, critical, and supercritical regions. Then, the corresponding dynamical correlation patterns and community structure are compared. In the critical region, we found some distinctive properties, namely high correlation and correlation switching, high modularity and a low number of modules, high stability of the dynamical functional connectivity, and moderate flexibility of the community structure across temporal scales. We also discuss how these characteristics might improve information processing of the brain.     

Dynamics of a hybrid system of a brain neural network and an artificial nonlinear oscillator

In the brain, many functional modules interact with each other to execute complex information processing. Understanding the nature of these interactions is necessary for understanding how the brain functions. In this study, to mimic interacting modules in the brain, we constructed a hybrid system mutually coupling a hippocampal CA3 network as an actual brain module and a radial isochron clock (RIC) simulated by a personal computer as an artificial module. Return map analysis of the CA3-RIC system's dynamics showed the mutual entrainment and complex dynamics dependent on the coupling modes. The phase response curve of CA3 was modeled regarding the CA3 as a nonlinear oscillator. Using the phase response curves of CA3 and RIC, we reconstructed return maps of the hybrid system's dynamics. Although the reconstructed return maps almost agreed with the experimental data, there were deviations dependent on the coupling mode. In particular, we noted that the deviation was smaller under the bidirectional coupling conditions than during the one-way coupling from RIC to CA3. These results suggest that brain modules may flexibly change their dynamical properties through interaction with other modules.     

Paradigm lost: reconsidering functional form and group hypotheses in marine ecology

Although functional form and functional group models for marine algae have been used extensively, there is little general literature support for these models, and many studies have shown that associated hypotheses are often incorrect. In functional form/group models, a wide range of ecological and physiological functions are assumed to be correlated with general algal form or morphology. In contrast, functional group approaches have been used most successfully in terrestrial and aquatic systems when groupings are based on a particular function rather than overall plant morphology, and when addressing ecosystem-level questions. In this type of functional group approach, a given set of species would likely be grouped differently depending on the function under consideration. Functional groupings are appropriate for many situations and questions, but not all. Certainly, grouping taxa by a particular function can be very useful and often necessary for many ecosystem-level questions and modeling, especially where qualitative results are more important than quantitative predictions, and when there are too many species in a system to consider them all individually. However, when one considers species–species interactions or questions about population biology, the specific responses of individual species must be considered. To make functional group models more useful, we recommend that groupings be based on specific functions (e.g. nutrient uptake rates, photosynthesis rates, herbivore resistance, disturbance resistance, etc.) rather than gross morphology. Explicit testing of performance of a particular function should be made before generalizations can be assumed, and groupings should be used for questions/approaches where they are most appropriate. If models fail when tested, they should be modified using the additional information to generate new hypotheses and models, and then retested.     

ModuleSearch: finding functional modules in a protein–protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein–protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein–protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.