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Motivation Gene regulation is responsible for controlling numerous physiological functions and dynamically responding to environmental fluctuations. Reconstructing the human network of gene regulatory interactions is thus paramount to understanding the cell functional organization across cell types, as well as to elucidating pathogenic processes and identifying molecular drug targets. Although significant effort has been devoted towards this direction, existing computational methods mainly rely on gene expression levels, possibly ignoring the information conveyed by mechanistic biochemical knowledge. Moreover, except for a few recent attempts, most of the existing approaches only consider the information of the organism under analysis, without exploiting the information of related model organisms. Results We propose a novel method for the reconstruction of the human gene regulatory network, based on a transfer learning strategy that synergically exploits information from human and mouse, conveyed by gene-related metabolic features generated in silico from gene expression data. Specifically, we learn a predictive model from metabolic activity inferred via tissue-specific metabolic modelling of artificial gene knockouts. Our experiments show that the combination of our transfer learning approach with the constructed metabolic features provides a significant advantage in terms of reconstruction accuracy, as well as additional clues on the contribution of each constructed metabolic feature. Availability and implementation The method, the datasets and all the results obtained in this study are available at: https://doi.org/10.6084/m9.figshare.c.5237687. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Gene network reconstruction is a bioinformatics task that aims at modelling the complex regulatory activities that may occur among genes. This task is typically solved by means of link prediction methods that analyze gene expression data. However, the reconstructed networks often suffer from a high amount of false positive edges, which are actually the result of indirect regulation activities due to the presence of common cause and common effect phenomena or, in other terms, due to the fact that the adopted inductive methods do not take into account possible causality phenomena. This issue is accentuated even more by the inherent presence of a high amount of noise in gene expression data. Existing methods for the identification of a transitive reduction of a network or for the removal of (possibly) redundant edges suffer from limitations in the structure of the network or in the nature/length of the indirect regulation, and often require additional pre-processing steps to handle specific peculiarities of the networks (e.g., cycles). Moreover, they are not able to consider possible community structures and possible similar roles of the genes in the network (e.g. hub nodes), which may change the tendency of nodes to be highly connected (and with which nodes) in the network. In this paper, we propose the method INLOCANDA, which learns an inductive predictive model for gene network reconstruction and overcomes all the mentioned limitations. In particular, INLOCANDA is able to (i) identify and exploit indirect relationships of arbitrary length to remove edges due to common cause and common effect phenomena; (ii) take into account possible community structures and possible similar roles by means of graph embedding. Experiments performed along multiple dimensions of analysis on benchmark, real networks of two organisms (E. coli and S. cerevisiae) show a higher accuracy with respect to the competitors, as well as a higher robustness to the presence of noise in the data, also when a huge amount of (possibly false positive) interactions is removed. Availability: http://www.di.uniba.it/~gianvitopio/systems/inlocanda/ [ABSTRACT FROM AUTHOR]

Motivation The reconstruction of gene regulatory networks (GRNs) from gene expression data has received increasing attention in recent years, due to its usefulness in the understanding of regulatory mechanisms involved in human diseases. Most of the existing methods reconstruct the network through machine learning approaches, by analyzing known examples of interactions. However, (i) they often produce poor results when the amount of labeled examples is limited, or when no negative example is available and (ii) they are not able to exploit information extracted from GRNs of other (better studied) related organisms, when this information is available. Results In this paper, we propose a novel machine learning method that overcomes these limitations, by exploiting the knowledge about the GRN of a source organism for the reconstruction of the GRN of the target organism, by means of a novel transfer learning technique. Moreover, the proposed method is natively able to work in the positive-unlabeled setting, where no negative example is available, by fruitfully exploiting a (possibly large) set of unlabeled examples. In our experiments, we reconstructed the human GRN, by exploiting the knowledge of the GRN of Mus musculus. Results showed that the proposed method outperforms state-of-the-art approaches and identifies previously unknown functional relationships among the analyzed genes. Availability and implementation http://www.di.uniba.it/∼mignone/systems/biosfer/index.html. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background: microRNAs (miRNAs) are a class of small non-coding RNAs which have been recognized as ubiquitous post-transcriptional regulators. The analysis of interactions between different miRNAs and their target genes is necessary for the understanding of miRNAs' role in the control of cell life and death. In this paper we propose a novel data mining algorithm, called HOCCLUS2, specifically designed to bicluster miRNAs and target messenger RNAs (mRNAs) on the basis of their experimentally-verified and/or predicted interactions. Indeed, existing biclustering approaches, typically used to analyze gene expression data, fail when applied to miRNA:mRNA interactions since they usually do not extract possibly overlapping biclusters (miRNAs and their target genes may have multiple roles), extract a huge amount of biclusters (difficult to browse and rank on the basis of their importance) and work on similarities of feature values (do not limit the analysis to reliable interactions). Results: To overcome these limitations, HOCCLUS2 i) extracts possibly overlapping biclusters, to catch multiple roles of both miRNAs and their target genes; ii) extracts hierarchically organized biclusters, to facilitate bicluster browsing and to distinguish between universe and pathway-specific miRNAs; iii) extracts highly cohesive biclusters, to consider only reliable interactions; iv) ranks biclusters according to the functional similarities, computed on the basis of Gene Ontology, to facilitate bicluster analysis. Conclusions: Our results show that HOCCLUS2 is a valid tool to support biologists in the identification of contextspecific miRNAs regulatory modules and in the detection of possibly unknown miRNAs target genes. Indeed, results prove that HOCCLUS2 is able to extract cohesiveness-preserving biclusters, when compared with competitive approaches, and statistically confirm (at a confidence level of 99%) that mRNAs which belong to the same biclusters are, on average, more functionally similar than mRNAs which belong to different biclusters. Finally, the hierarchy of biclusters provides useful insights to understand the intrinsic hierarchical organization of miRNAs and their potential multiple interactions on target genes. [ABSTRACT FROM AUTHOR]