Simultaneous learning of individual microRNA-gene interactions and regulatory comodules.

BACKGROUND: MicroRNAs (miRNAs) function in post-transcriptional regulation of gene expression by binding to target messenger RNAs (mRNAs). Because of the key part that miRNAs play, understanding the correct regulatory role of miRNAs in diverse patho-physiological conditions is of great interest. Although it is known that miRNAs act combinatorially to regulate genes, precise identification of miRNA-gene interactions and their specific functional roles in regulatory comodules remains a challenge. We developed THEIA, an effective method for simultaneously predicting miRNA-gene interactions and regulatory comodules, which group functionally related miRNAs and genes via non-negative matrix factorization (NMF). RESULTS: We apply THEIA to RNA sequencing data from breast invasive carcinoma samples and demonstrate its effectiveness in discovering biologically significant regulatory comodules that are significantly enriched in spatial miRNA clusters, biological pathways, and various cancers. CONCLUSIONS: THEIA is a theoretically rigorous optimization algorithm that simultaneously predicts the strength and direction (i.e., up-regulation or down-regulation) of the effect of modules of miRNAs on a gene. We posit that if THEIA is capable of recovering known clusters of genes and miRNA, then the clusters found by our method not previously identified by literature are also likely to have biological significance. We believe that these novel regulatory comodules found by our method will be a springboard for further research into the specific functional roles of these new functional ensembles of miRNAs and genes,especially those related to diseases like breast cancer.

Federation in genomics pipelines: techniques and challenges.

Federation is a popular concept in building distributed cyberinfrastructures, whereby computational resources are provided by multiple organizations through a unified portal, decreasing the complexity of moving data back and forth among multiple organizations. Federation has been used in bioinformatics only to a limited extent, namely, federation of datastores, e.g. SBGrid Consortium for structural biology and Gene Expression Omnibus (GEO) for functional genomics. Here, we posit that it is important to federate both computational resources (CPU, GPU, FPGA, etc.) and datastores to support popular bioinformatics portals, with fast-increasing data volumes and increasing processing requirements. A prime example, and one that we discuss here, is in genomics and metagenomics. It is critical that the processing of the data be done without having to transport the data across large network distances. We exemplify our design and development through our experience with metagenomics-RAST (MG-RAST), the most popular metagenomics analysis pipeline. Currently, it is hosted completely at Argonne National Laboratory. However, through a recently started collaborative National Institutes of Health project, we are taking steps toward federating this infrastructure. Being a widely used resource, we have to move toward federation without disrupting 50 K annual users. In this article, we describe the computational tools that will be useful for federating a bioinformatics infrastructure and the open research challenges that we see in federating such infrastructures. It is hoped that our manuscript can serve to spur greater federation of bioinformatics infrastructures by showing the steps involved, and thus, allow them to scale to support larger user bases.

Tiresias: Context-sensitive Approach to Decipher the Presence and Strength of MicroRNA Regulatory Interactions.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate expression of target messenger RNAs (mRNAs) post-transcriptionally. Understanding the precise regulatory role of miRNAs is of great interest since miRNAs have been shown to play an important role in development, diseases, and other biological processes. Early work on miRNA target prediction has focused on static sequence-driven miRNA-mRNA complementarity. However, recent research also utilizes expression-level data to study context-dependent regulation effects in a more dynamic, physiologically-relevant setting. Methods: We propose a novel artificial neural network (ANN) based method, named Tiresias, to predict such targets in a context-dependent manner by combining sequence and expression data. In order to predict the interacting pairs among miRNAs and mRNAs and their regulatory weights, we develop a two-stage ANN and present how to train it appropriately. Tiresias is designed to study various regulation models, ranging from a simple linear model to a complex non-linear model. Tiresias has a single hyper-parameter to control the sparsity of miRNA-mRNA interactions, which we optimize using Bayesian optimization. Results: Tiresias performs better than existing computational methods such as GenMiR++, Elastic Net, and PIMiM, achieving an F1 score of >0.8 for a certain level of regulation strength. For the TCGA breast invasive carcinoma dataset, Tiresias results in the rate of up to 82% in detecting the experimentally-validated interactions between miRNAs and mRNAs, even if we assume that true regulations may result in a low level of regulation strength. Conclusion: Tiresias is a two-stage ANN, computational method that deciphers context-dependent microRNA regulatory interactions. Experiment results demonstrate that Tiresias outperforms existing solutions and can achieve a high F1 score. Source code of Tiresias is available at https://bitbucket.org/cellsandmachines/.