Epistasis analysis with global transcriptional phenotypes

Driessche, Nancy Van; Demšar, Janez; Booth, Ezgi O.; Hill, P J; Juvan, Peter; Zupan, Blaž; Kuspa, Adam; Shaulsky, Gad

doi:10.1038/ng1545

Cited by 101 publications

(92 citation statements)

References 45 publications

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“…The latter is a surrogate measure of cell physiology and an indicator of differences between mutant strains (15)(16)(17)(18)(19)(20). Recently, the organism has been used as a model for drug target discovery using genetics and genomic approaches (1, 2).…”

Section: Discussionmentioning

confidence: 99%

“…Transcriptional profiling with cDNA microarrays can identify groups of genes whose expression is altered by experimental treatments. It is also used as a surrogate measure of cell physiology and to detect differences between mutant strains (15)(16)(17)(18)(19)(20). The availability of two isogenic cisplatin-resistant strains with alterations in sphingolipid metabolism allowed us to compare the mutants' transcriptional responses to that of wildtype cells after cisplatin exposure and to understand how the mutations affected the response.…”

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confidence: 99%

“…These findings suggest that the cellular response to cisplatin is regulated and reproducible. Transcriptional analysis with microarrays is an established indicator of cell physiology in D. discoideum (18,19). Thus, we tested whether cisplatin causes orderly physiological changes by examining the transcriptional response of cells to cisplatin treatment.…”

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confidence: 99%

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Global transcriptional responses to cisplatin in Dictyostelium discoideum identify potential drug targets

Driessche¹,

Alexander

Kuspa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Dictyostelium discoideum is a useful model for studying mechanisms of cisplatin drug sensitivity. Our previous findings, that mutations in sphingolipid metabolism genes confer cisplatin resistance in D. discoideum and in human cells, raised interest in the resistance mechanisms and their implications for cisplatin chemotherapy. Here we used expression microarrays to monitor physiological changes and to identify pathways that are affected by cisplatin treatment of D. discoideum. We found >400 genes whose regulation was altered by cisplatin treatment of wild-type cells, including groups of genes that participate in cell proliferation and in nucleotide and protein metabolism, showing that the cisplatin response is orderly and multifaceted. Transcriptional profiling of two isogenic cisplatin-resistant mutants, impaired in different sphingolipid metabolism steps, showed that the effect of cisplatin treatment was greater than the effect of the mutations, indicating that cisplatin resistance in the mutants is due to specific abilities to overcome the drug effects rather than to general drug insensitivity. Nevertheless, the mutants exhibited significantly different responses to cisplatin compared with the parent, and >200 genes accounted for that difference. Mutations in five cisplatin response genes (sgkB, csbA, acbA, smlA, and atg8) resulted in altered drug sensitivity, implicating novel pathways in cisplatin response. Our data illustrate how modeling complex cellular responses to drugs in genetically stable and tractable systems can uncover new targets with the potential for improving chemotherapy.drug resistance ͉ sphingolipids ͉ sphingosine kinase ͉ sphingosine-1-phosphate lyase ͉ transcriptional profiling D ictyostelium discoideum is well known for studies of cell and developmental biology and is gaining interest as a model for studying human disease, including cancer (1). A substantial body of work has accumulated using D. discoideum to identify genes and proteins associated with resistance to the anti-cancer drug cisplatin (2).Cisplatin [cis-diamminedichloroplatinum(II)] is used to treat a variety of solid tumors (3), but efficacy is often limited by drug resistance (4). Studies in human tumor cells and cell lines have implicated a number of resistance mechanisms and demonstrated that resistance is multifaceted (5).D. discoideum provides a genetically tractable system to the problem of cisplatin resistance. It is a eukaryote with cellular properties similar to those of human cells (6). Its genome is sequenced, and many genes are homologous to human genes (7). Using insertional mutagenesis screens (8), we isolated mutants with single gene disruptions that have decreased sensitivity to cisplatin (9). One of these strains was null for the sphingosine-1-phosphate (S-1-P) lyase gene sglA, establishing the first link between sphingolipid metabolism and cisplatin sensitivity and defining S-1-P lyase as a potential target for controlling cisplatin sensitivity.S-1-P synthesis is catalyzed by sphingosine kinase from sphin...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Global transcriptional responses to cisplatin in Dictyostelium discoideum identify potential drug targets

Driessche¹,

Alexander

Kuspa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Such nonlinear character of gene interactions is often named as epistasis (Van Driessche et al, 2005;Sanjuán and Elena, 2006;Collins et al, 2007, Zheng et al, 2010, Elena et al, 2010. We can understand the functional role of any component by looking at the consequences of perturbing it.…”

Section: Introductionmentioning

confidence: 99%

Evolved Modular Epistasis in Artificial Organisms

Valverde

Solé²,

Elena³

2012

Artificial Life 13

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How does complexity evolve in artificial and natural systems? A central concept within genetic systems is epistasis, namely the modulation of the effects of a given gene by one or several other genes. Epistasis is known to have an impact on many features of organisms, from recombination and sex to the ruggedness of the underlying fitness landscapes. However, the multi-scale nature of evolution and organisms makes often difficult to properly characterize epistatic interactions. Here we study the hierarchical organization of epistatic interactions between machine instructions in evolved digital organisms. We present a new quantitative approach to discover epistatic interactions that is able to capture the presence and role of groups of epistatic modules. Therefore, it thus takes into account the intrinsic nested nature of individual complexity. We found evidences of modular epistasis in avidians, with some modules having a tendency toward antagonistic epistasis while others show the opposite epistatic sign. We also found that this modular organization was positively correlated to organismal robustness.

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“…[18]. (b) Network inference from PAK pathway [67] using NICO, in the presence of a prior known end points in each path [68]. (c) The building block of cGraph from Ref.…”

Section: Reconstruction Of Biological Networkmentioning

confidence: 99%