NetControl4BioMed: a pipeline for biomedical data acquisition and analysis of network controllability.

BACKGROUND: Network controllability focuses on discovering combinations of external interventions that can drive a biological system to a desired configuration. In practice, this approach translates into finding a combined multi-drug therapy in order to induce a desired response from a cell; this can lead to developments of novel therapeutic approaches for systemic diseases like cancer. RESULT: We develop a novel bioinformatics data analysis pipeline called NetControl4BioMed based on the concept of target structural control of linear networks. Our pipeline generates novel molecular interaction networks by combining pathway data from various public databases starting from the user's query. The pipeline then identifies a set of nodes that is enough to control a given, user-defined set of disease-specific essential proteins in the network, i.e., it is able to induce a change in their configuration from any initial state to any final state. We provide both the source code of the pipeline as well as an online web-service based on this pipeline http://combio.abo.fi/nc/net_control/remote_call.php . CONCLUSION: The pipeline can be used by researchers for controlling and better understanding of molecular interaction networks through combinatorial multi-drug therapies, for more efficient therapeutic approaches and personalised medicine.

Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.

Identification of genetic markers with synergistic survival effect in cancer.

BACKGROUND: Cancers are complex diseases arising from accumulated genetic mutations that disrupt intracellular signaling networks. While several predisposing genetic mutations have been found, these individual mutations account only for a small fraction of cancer incidence and mortality. With large-scale measurement technologies, such as single nucleotide polymorphism (SNP) microarrays, it is now possible to identify combinatorial effects that have significant impact on cancer patient survival. RESULTS: The identification of synergetic functioning SNPs on genome-scale is a computationally daunting task and requires advanced algorithms. We introduce a novel algorithm, Geninter, to identify SNPs that have synergetic effect on survival of cancer patients. Using a large breast cancer cohort we generate a simulator that allows assessing reliability and accuracy of Geninter and logrank test, which is a standard statistical method to integrate genetic and survival data. CONCLUSIONS: Our results show that Geninter outperforms the logrank test and is able to identify SNP-pairs with synergetic impact on survival.

The phosphorylation of the heat shock factor as a modulator for the heat shock response.

The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis of hsp is highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation of hsf's. Experimental evidence shows a connection between the hyper-phosphorylation of hsfs and the transactivation of the hsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.