Integrative methods for reconstruction of dynamic networks in chondrogenesis

Application of human mesenchymal stem cells represents a promising approach in the field of regenerative medicine. Specific stimulation can give rise to chondrocytes, osteocytes or adipocytes. Investigation of the underlying biological processes which induce the observed cellular differentiation is essential to efficiently generate specific tissues for therapeutic purposes. Upon treatment with diverse stimuli, gene expression levels of cultivated human mesenchymal stem cells were monitored using time series microarray experiments for the three lineages. Application of gene network inference is a common approach to identify the regulatory dependencies among a set of investigated genes. This thesis applies the NetGenerator V2.0 tool, which is capable to deal with multiple time series data, which investigates the effect of multiple external stimuli. The applied model is based on a system of linear ordinary differential equations, whose parameters are optimised to reproduce the given time series datasets. Several procedures in the inference process were adapted in this new version in order to allow for the integration of multiple datasets. Network inference was applied on in silico network examples as well as on multi-experiment microarray data of mesenchymal stem cells. The resulting chondrogenesis model was evaluated on the basis of several features including the model adaptation to the data, total number of connections, proportion of connections associated with prior knowledge and the model stability in a resampling procedure. Altogether, NetGenerator V2.0 has provided an automatic and efficient way to integrate experimental datasets and to enhance the interpretability and reliability of the resulting network. In a second chondrogenesis model, the miRNA and mRNA time series data were integrated for the purpose of network inference. One hypothesis of the model was verified by experiments, which demonstrated the negative effect of miR-524-5p on downstream genes

동시조절 유전적 상호작용 발굴을 위한 하이퍼그래프 모델

학위논문 (박사)-- 서울대학교 대학원 : 협동과정 생물정보학전공, 2014. 2. 장병탁.A comprehensive understanding of biological systems requires the analysis of higher-order interactions among many genomic factors. Various genomic factors cooperate to affect biological processes including cancer occurrence, progression and metastasis. However, the complexity of genomic interactions presents a major barrier to identifying their co-regulatory roles and functional effects. Thus, this dissertation addresses the problem of analyzing complex relationships among many genomic factors in biological processes including cancers. We propose a hypergraph approach for modeling, learning and extracting: explicitly modeling higher-order genomic interactions, efficiently learning based on evolutionary methods, and effectively extracting biological knowledge from the model. A hypergraph model is a higher-order graphical model explicitly representing complex relationships among many variables from high-dimensional data. This property allows the proposed model to be suitable for the analysis of biological and medical phenomena characterizing higher-order interactions between various genomic factors. This dissertation proposes the advanced hypergraph-based models in terms of the learning methods and the model structures to analyze large-scale biological data focusing on identifying co-regulatory genomic interactions on a genome-wide level. We introduce an evolutionary approach based on information-theoretic criteria into the learning mechanisms for efficiently searching a huge problem space reflecting higher-order interactions between factors. This evolutionary learning is explained from the perspective of a sequential Bayesian sampling framework. Also, a hierarchy is introduced into the hypergraph model for modeling hierarchical genomic relationships. This hierarchical structure allows the hypergraph model to explicitly represent gene regulatory circuits as functional blocks or groups across the level of epigenetic, transcriptional, and post-transcriptional regulation. Moreover, the proposed graph-analyzing method is able to grasp the global structures of biological systems such as genomic modules and regulatory networks by analyzing the learned model structures. The proposed model is applied to analyzing cancer genomics considered as a major topic in current biology and medicine. We show that the performance of our model competes with or outperforms state-of-the-art models on multiple cancer genomic data. Furthermore, the propose model is capable of discovering new or hidden patterns as candidates of potential gene regulatory circuits such as gene modules, miRNA-mRNA networks, and multiple genomic interactions, associated with the specific cancer. The results of these analysis can provide several crucial evidences that can pave the way for identifying unknown functions in the cancer system. The proposed hypergraph model will contribute to elucidating core regulatory mechanisms and to comprehensive understanding of biological processes including cancers.Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i 1 Introduction 1.1 Background and Motivation . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Problems to be Addressed . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.3 The Proposed Approach and its Contribution . . . . . . . . . . . . . . 4 1.4 Organization of the Dissertation . . . . . . . . . . . . . . . . . . . . . 6 2 Related Work 2.1 Analysis of Co-Regulatory Genomic Interactions from Omics Data . . 9 2.2 Probabilistic Graphical Models for Biological Problems . . . . . . . . 11 2.2.1 Bayesian Networks . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2.2 Markov Random Fields . . . . . . . . . . . . . . . . . . . . . . 13 2.2.3 Hidden Markov Models . . . . . . . . . . . . . . . . . . . . . . 15 2.3 Higher-order Graphical Models for Biological Problems . . . . . . . . 16 2.3.1 Higher-Order Models . . . . . . . . . . . . . . . . . . . . . . . 16 2.3.2 Hypergraphs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3 Hypergraph Classifiers for Identifying Prognostic Modules in Cancer 3.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 3.2 Analyzing Gene Modules for Cancer Prognosis Prediction . . . . . . 24 3.3 Hypergraph Classifiers for Identifying Cancer Gene Modules . . . . 26 3.3.1 Hypergraph Classifiers . . . . . . . . . . . . . . . . . . . . . . 26 3.3.2 Bayesian Evolutionary Algorithm . . . . . . . . . . . . . . . . 27 3.3.3 Bayesian Evolutionary Learning for Hypergraph Classifiers . 29 3.4 Predicting Cancer Clinical Outcomes Based on Gene Modules . . . . 34 3.4.1 Data and Experimental Settings . . . . . . . . . . . . . . . . . 34 3.4.2 Prediction Performance . . . . . . . . . . . . . . . . . . . . . . 36 3.4.3 Model Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 3.4.4 Identification of Prognostic Gene Modules . . . . . . . . . . . 44 3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4 Hypergraph-based Models for Constructing Higher-Order miRNA-mRNA Interaction Networks in Cancer 4.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.2 Analyzing Relationships between miRNAs and mRNAs from Heterogeneous Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.3 Hypergraph-based Models for Identifying miRNA-mRNA Interactions 57 4.3.1 Hypergraph-based Models . . . . . . . . . . . . . . . . . . . . 57 4.3.2 Learning Hypergraph-based Models . . . . . . . . . . . . . . . 61 4.3.3 Building Interaction Networks from Hypergraphs . . . . . . . 64 4.4 Constructing miRNA-mRNA Interaction Networks Based on Higher- Order Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 4.4.1 Data and Experimental Settings . . . . . . . . . . . . . . . . . 66 4.4.2 Classification Performance . . . . . . . . . . . . . . . . . . . . 68 4.4.3 Model Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . 70 CONTENTS iii 4.4.4 Constructed Higher-Order miRNA-mRNA Interaction Networks in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . 74 4.4.5 Functional Analysis of the Constructed Interaction Networks 78 4.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 5 Hierarchical Hypergraphs for Identifying Higher-Order Genomic Interactions in Multilevel Regulation 5.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.2 Analyzing Epigenetic and Genetic Interactions from Multiple Genomic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 5.3 Hierarchical Hypergraphs for Identifying Epigenetic and Genetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 5.3.1 Hierarchical Hypergraphs . . . . . . . . . . . . . . . . . . . . . 92 5.3.2 Learning Hierarchical Hypergraphs . . . . . . . . . . . . . . . 95 5.4 Identifying Higher-Order Genomic Interactions in Multilevel Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 5.4.1 Data and Experimental Settings . . . . . . . . . . . . . . . . . 100 5.4.2 Identified Higher-Order miRNA-mRNA Interactions Induced by DNA Methylation in Ovarian Cancer . . . . . . . . . . . . 102 5.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 6 Concluding Remarks 6.1 Summary of the Dissertation . . . . . . . . . . . . . . . . . . . . . . . 107 6.2 Directions for Further Research . . . . . . . . . . . . . . . . . . . . . . 109 Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 초록 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Docto

Characterizing the Huntington's disease, Parkinson's disease, and pan-neurodegenerative gene expression signature with RNA sequencing

Huntington's disease (HD) and Parkinson's disease (PD) are devastating neurodegenerative disorders that are characterized pathologically by degeneration of neurons in the brain and clinically by loss of motor function and cognitive decline in mid to late life. The cause of neuronal degeneration in these diseases is unclear, but both are histologically marked by aggregation of specific proteins in specific brain regions. In HD, fragments of a mutant Huntingtin protein aggregate and cause medium spiny interneurons of the striatum to degenerate. In contrast, PD brains exhibit aggregation of toxic fragments of the alpha synuclein protein throughout the central nervous system and trigger degeneration of dopaminergic neurons in the substantia nigra. Considering the commonalities and differences between these diseases, identifying common biological patterns across HD and PD as well as signatures unique to each may provide significant insight into the molecular mechanisms underlying neurodegeneration as a general process. State-of-the-art high-throughput sequencing technology allows for unbiased, whole genome quantification of RNA molecules within a biological sample that can be used to assess the level of activity, or expression, of thousands of genes simultaneously. In this thesis, I present three studies characterizing the RNA expression profiles of post-mortem HD and PD subjects using high-throughput mRNA sequencing data sets. The first study describes an analysis of differential expression between HD individuals and neurologically normal controls that indicates a widespread increase in immune, neuroinflammatory, and developmental gene expression. The second study expands upon the first study by making methodological improvements and extends the differential expression analysis to include PD subjects, with the goal of comparing and contrasting HD and PD gene expression profiles. This study was designed to identify common mechanisms underlying the neurodegenerative phenotype, transcending those of each unique disease, and has revealed specific biological processes, in particular those related to NFkB inflammation, common to HD and PD. The last study describes a novel methodology for combining mRNA and miRNA expression that seeks to identify associations between mRNA-miRNA modules and continuous clinical variables of interest, including CAG repeat length and clinical age of onset in HD

Recent Developments in Cancer Systems Biology

This ebook includes original research articles and reviews to update readers on the state of the art systems approach to not only discover novel diagnostic and prognostic biomarkers for several cancer types, but also evaluate methodologies to map out important genomic signatures. In addition, therapeutic targets and drug repurposing have been emphasized for a variety of cancer types. In particular, new and established researchers who desire to learn about cancer systems biology and why it is possibly the leading front to a personalized medicine approach will enjoy reading this book

MicroRNA Interaction Networks

La tesi di Giorgio Bertolazzi è incentrata sullo sviluppo di nuovi algoritmi per la predizione dei legami miRNA-mRNA. In particolare, un algoritmo di machine-learning viene proposto per l'upgrade del web tool ComiR; la versione originale di ComiR considerava soltanto i siti di legame dei miRNA collocati nella regione 3'UTR dell'RNA messaggero. La nuova versione di ComiR include nella ricerca dei legami la regione codificante dell'RNA messaggero.Bertolazzi’s thesis focuses on developing and applying computational methods to predict microRNA binding sites located on messenger RNA molecules. MicroRNAs (miRNAs) regulate gene expression by binding target messenger RNA molecules (mRNAs). Therefore, the prediction of miRNA binding is important to investigate cellular processes. Moreover, alterations in miRNA activity have been associated with many human diseases, such as cancer. The thesis explores miRNA binding behavior and highlights fundamental information for miRNA target prediction. In particular, a machine learning approach is used to upgrade an existing target prediction algorithm named ComiR; the original version of ComiR considers miRNA binding sites located on mRNA 3’UTR region. The novel algorithm significantly improves the ComiR prediction capacity by including miRNA binding sites located on mRNA coding regions

Gene Regulatory Network Inference Using Machine Learning Techniques

Systems Biology is a field that models complex biological systems in order to better understand the working of cells and organisms. One of the systems modeled is the gene regulatory network that plays the critical role of controlling an organism's response to changes in its environment. Ideally, we would like a model of the complete gene regulatory network. In recent years, several advances in technology have permitted the collection of an unprecedented amount and variety of data such as genomes, gene expression data, time-series data, and perturbation data. This has stimulated research into computational methods that reconstruct, or infer, models of the gene regulatory network from the data. Many solutions have been proposed, yet there remain open challenges in utilising the range of available data as it is inherently noisy, and must be integrated by the inference techniques. The thesis seeks to contribute to this discourse by investigating challenges of performance, scale, and data integration. We propose a new algorithm BENIN that views network inference as feature selection to address issues of scale, that uses elastic net regression for improved performance, and adapts elastic net to integrate different types of biological data. The BENIN algorithm is benchmarked on a synthetic dataset from the DREAM4 challenge, and on real expression data for the human HeLa cell cycle. On the DREAM4 dataset BENIN out-performed all DREAM4 competitors on the size 100 subchallenge, and is also competitive with more recent state-of-the-art methods. Moreover, on the HeLa cell cycle data, BENIN could infer known regulatory interactions and propose new interactions that warrant further experimental investigation. Keys words: gene regulatory network, network inference, feature selection, elastic net regression