Chapter 5. Use Scenarios

Highly connected proteins have stable steady-state distribution of gene expression

Title: On a fundamental structure of gene networks in living cells

Summary: This study develops a thermodynamic-like theoretical framework to analyze protein networks and gene expression patterns. Using this methodology, they find a dependence of the steady-state stability of transcript levels and the connectivity in STRING networks. The findings agree with the observation that essential genes have a low variability of expression and emphasize the role of stochasticity and robustness in the control of expression. The authors suggest that genes can be grouped into two categories, high and low expression, which are stable, versus adaptable to biological stimuli.

Link: Kravchenko-Balasha, N et al. PNAS. 2012.

Searching for candidate genes involved in the immune response to gluten

Title: Integration of genetic and immunological insights into a model of celiac disease pathogenesis

Summary: Celiac disease (CD) is an auto-immune condition which may cause gastrointestinal and nutritional problems. The authors of this review article use STRING to look for interactions of genes that are known to be involved in CD. This results in 40 candidate genes that are likely to be involved in the progression of the disease. Since the levels the marker genes of CD is heterogeneous, several different genes may be the cause of the condition.

Link: Abadie, V et al. Annu. Rev. Immunol. 2011.

Identifying candidates for unknown enzyme in a pathway

Title: Biosynthesis and functions of bacillithiol, a major low-molecular-weight thiol in Bacilli

Summary: Bacillithiol (BSH) is a low-molecular-weight thiol in bacteria (Bacilli family). It is synthesized by a not fully characterized pathway. The authors used STRING to identify candidates for an unknown enzyme using known components of the pathway as input query. The co-occurence and the fusion channel revealed a potential candidate for the enzyme. Experiments could then confirm that the functionality indeed was essential for the pathway.

Gaballa, A et al. PNAS. 2010.

Using STRING to narrow search space for two-locus epistatis

Title: Using biological networks to search for interacting loci in genome-wide association studies

Summary: The aim of this study was to search for combinations of pairs of SNPs that cause disease (two-locus epistatis). Testing all combinations is computationally expensive. By limiting the number of search possibilities to known protein-protein interactions from STRING the search space was drastically reduced. Furthermore, by only accessing likely candidates of protein interactions, low significance of interaction due to correcting for multiple comparisons is alleviated.

Emily, M et al. Eur J Hum Genet. 2009.

Using STRING to show network connectivity

Title: Lysine acetylation targets protein complexes and co-regulates major cellular functions

Summary: Lysine acetylation is a post-translational modification that regulate gene expression. This study show that lysine acetylation preferentially targets large macro-molecular complexes and has a broad regulatory scope comparable with other post-translational modifications. By using STRING the authors show that the acetylome has significantly higher network connectivity than random (~6 interactions per node, random is less than 3)

Choudhary, C et al. Science. 2009.

STRING as a general purpose database

Title: Phylogeny of the CDC25 homology domain reveals rapid differentiation of Ras pathways between early animals and fungi

Summary: In this study the evolutionary history of CDC25 homology domain was investigated. The STRING database was used to acquire the sequence information for a number of genomes, showing how STRING can be used as a as general database. This is particularly useful if the user download the entire dataset by signing the academic license agreement.

van Dam, TJ et al. Cell Signal. 2009.

STRING to guide experiments

Title: The thioredoxin-like protein rod-derived cone viability factor (RdCVFL) interacts with TAU and inhibits its phosphorylation in the retina

Summary: This study is a characterization of the Rod-derived Cone Viability Factor (RdCVFL) signaling pathway involved in neuronal cell death mediated by oxidative stress. STRING was used to identify 90 proteins interacting with RdCVFL. These were examined for interactions using a cell-based assay. The authors show that RdCVFL inhibits the phosphorylation of the microtubule binding protein Tau. In vitro, RdCVFL protects Tau from oxidative damage, which is implicated in retinal degeneration.

Fridlich, R et al. Mol Cell Proteomics. 2009.

Prioritizing functional assignments in RNAi screens using interaction network data

Title: A network-based integrative approach to prioritize reliable hits from multiple genome-wide RNAi screens in Drosophila

Summary: RNA interference (RNAi) screening can be used to infer the functionally of genes in an organism. The results from such screens often contain errors. Wang et al. suggest a method based on a scoring function for integrating STRING network information to indicate false positives and false negatives associated with RNAi screens. Thereby, suggesting optimal candidates for follow-up experimental validation.

Wang, L et al. BMC Genomics. 2009.