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Summary Gene expression alterations and potentially underlying gene copy number mutations can be measured routinely in the wet lab, but it is still extremely challenging to quantify impacts of altered genes on clinically relevant characteristics to predict putative driver genes. We developed the R package regNet that utilizes gene expression and copy number data to learn regulatory networks for the quantification of potential impacts of individual gene expression alterations on user-defined target genes via network propagation. We demonstrate the value of regNet by identifying putative major regulators that distinguish pilocytic from diffuse astrocytomas and by predicting putative impacts of glioblastoma-specific gene copy number alterations on cell cycle pathway genes and patient survival. Availability and implementation regNet is available for download at https://github.com/seifemi/regNet under GNU GPL-3. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation: Methylation of cytosines in DNA is an important epigenetic mechanism involved in transcriptional regulation and preservation of genome integrity in a wide range of eukaryotes. Immunoprecipitation of methylated DNA followed by hybridization to genomic tiling arrays (MeDIP-chip) is a cost-effective and sensitive method for methylome analyses. However, existing bioinformatics methods only enable a binary classification into unmethylated and methylated genomic regions, which limit biological interpretations. Indeed, DNA methylation levels can vary substantially within a given DNA fragment depending on the number and degree of methylated cytosines. Therefore, a method for the identification of more than two methylation states is highly desirable. Results: Here, we present a three-state hidden Markov model (MeDIP-HMM) for analyzing MeDIP-chip data. MeDIP-HMM uses a higher-order state-transition process improving modeling of spatial dependencies between chromosomal regions, allows a simultaneous analysis of replicates and enables a differentiation between unmethylated, methylated and highly methylated genomic regions. We train MeDIP-HMM using a Bayesian Baum–Welch algorithm, integrating prior knowledge on methylation levels. We apply MeDIP-HMM to the analysis of the Arabidopsis root methylome and systematically investigate the benefit of using higher-order HMMs. Moreover, we also perform an in-depth comparison study with existing methods and demonstrate the value of using MeDIP-HMM by comparisons to current knowledge on the Arabidopsis methylome. We find that MeDIP-HMM is a fast and precise method for the analysis of methylome data, enabling the identification of distinct DNA methylation levels. Finally, we provide evidence for the general applicability of MeDIP-HMM by analyzing promoter DNA methylation data obtained for chicken. Availability: MeDIP-HMM is available as part of the open-source Java library Jstacs (www.jstacs.de/index.php/MeDIP-HMM). Data files are available from the Jstacs website. Contact: seifert@ipk-gatersleben.de Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation: Changes in gene expression levels play a central role in tumors. Additional information about the distribution of gene expression levels and distances between adjacent genes on chromosomes should be integrated into the analysis of tumor expression profiles. Results: We use a Hidden Markov Model with distance-scaled transition matrices (DSHMM) to incorporate chromosomal distances of adjacent genes on chromosomes into the identification of differentially expressed genes in breast cancer. We train the DSHMM by integrating prior knowledge about potential distributions of expression levels of differentially expressed and unchanged genes in tumor. We find that especially the combination of these data and to a lesser extent the modeling of distances between adjacent genes contribute to a substantial improvement of the identification of differentially expressed genes in comparison to other existing methods. This performance benefit is also supported by the identification of genes well known to be associated with breast cancer. That suggests applications of DSHMMs for screening of other tumor expression profiles. Availability: The DSHMM is available as part of the open-source Java library Jstacs (www.jstacs.de/index.php/DSHMM). Contact: seifert@ipk-gatersleben.de Supplementary information: Supplementary data are available at Bioinformatics online. Supplementary data files are available at the Jstacs's web site.