Systematic screens for human disease genes, from yeast to human and back

European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.
Molecular BioSystems (Impact Factor: 3.21). 02/2008; 4(1):18-29. DOI: 10.1039/b709494a
Source: PubMed


Systematic screens for human disease genes have emerged in recent years, due to the wealth of information provided by genome sequences and large scale datasets. Here we review how integration of genomic data in yeast and human is helping to elucidate the genetic basis of mitochondrial diseases. The identification of nearly all yeast mitochondrial proteins and many of their functional interactions provides insight into the role of mitochondria in cellular processes. This information enables prioritization of the candidate genes underlying mitochondrial disorders. In an iterative fashion, the link between predicted human candidate genes and their disease phenotypes can be experimentally tested back in yeast.

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    • "Indeed, not only most of the basic cellular functions are conserved from yeast to humans, but also the diseases' key players themselves are often conserved: it is indeed estimated that at least 30% of the genes associated with human diseases have functional homologs in the S. cerevisiae genome [8]. For all these reasons, yeast has been increasingly used as a model and tool for biomedical research over the past one or two decades [9] [10]. "
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    ABSTRACT: Cross-complementation studies offer the possibility to overcome limitations imposed by the inherent complexity of multicellular organisms in the study of human diseases, by taking advantage of simpler model organisms like the budding yeast Saccharomyces cerevisiae. This review deals with, (1) the use of S. cerevisiae as a model organism to study human diseases, (2) yeast-based screening systems for the detection of diseases modifiers, (3) Hailey-Hailey as an example of a calcium-related disease, and (4) the presentation of a yeast-based model to search for chemical modifiers of Hailey-Hailey disease. The preliminary experimental data presented and discussed here show that it is possible to use yeast as a model system for Hailey-Hailey disease and suggest that in all likelihood, yeast has the potential to reveal candidate drugs for the treatment of this disorder. This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease.
    Biochimica et Biophysica Acta 02/2014; 1843(10). DOI:10.1016/j.bbamcr.2014.02.011 · 4.66 Impact Factor
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    • "This forms the basis for an original immune-based therapeutic strategy to selectively target EBV-infected cells, including EBV-carrying tumor cells. The versatile genetic flexibility of the budding yeast Saccharomyces cerevisiae and the high degree of conservation between yeast and mammalian cellular processes have made S. cerevisiae an invaluable tool for modeling human diseases (Bach et al., 2003; Bach et al., 2006; Bilsland et al., 2013; Blondel, 2012; Couplan et al., 2011; Mager and Winderickx, 2005; Perocchi et al., 2008), as well as for identifying and characterizing cellular pathways involved in these disorders and thereby new therapeutic targets (Giorgini et al., 2005; Louie et al., 2012). "
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    ABSTRACT: Epstein-Barr virus (EBV) is tightly associated to certain human cancers but there is of today no specific treatment against EBV-related diseases. The EBV-encoded EBNA1 protein is essential to maintain viral episomes and for viral persistence. EBNA1 is expressed in all EBV infected cells and is highly antigenic. All infected individuals, including cancer patients, have CD8(+) T cells directed towards EBNA1 epitopes, yet the immune system fails to detect and destroy cells harboring the virus. EBV's immune evasion depends on the capacity of the Gly-Ala repeat (GAr) domain of EBNA1 to inhibit the translation of its own mRNA in cis, thereby limiting the production of EBNA1-derived antigenic peptides presented by the Major Histocompatibility Complex (MHC) class I pathway. Here we establish a yeast-based assay for monitoring GAr-dependent inhibition of translation. Using this assay we identify doxorubicin (DXR) as a compound that specifically interferes with the GAr effect on translation in yeast. DXR targets the topoisomerase II/DNA complexes and thereby causes genomic damage. We show, however, that the genotoxic effect of DXR and various analogues thereof is uncoupled from the effect on GAr-mediated translation control. This is further supported by the observation that etoposide and teniposide, representing another class of topoisomerase II/DNA targeting drugs, have no effect on GAr-mediated translation control. DXR and active analogues stimulate in a GAr-dependent manner EBNA1 expression in mammalian cells and overcome GAr-dependent restriction of MHC class I antigen presentation. These results validate our approach as an effective high-throughput screening assay to identify drugs that interfere with EBV immune evasion and, thus, constitute candidates for treating EBV-related diseases, in particular EBV-associated cancers.
    Disease Models and Mechanisms 02/2014; 7(4). DOI:10.1242/dmm.014308 · 4.97 Impact Factor
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    • "Second, the relative ease of genetic manipulation in S. cerevisiae, as well as the growing use of zinc finger and TALE nucleases for targeted genome editing in higher eukaryotes (Miller et al., 2011; Urnov et al., 2010), may allow the study of position effects involving other genes beyond that presented by the kanMX cassette. In yeast, employing well-established methods for exchanging the kanMX marker with an exogenous DNA sequence (Goldstein and McCusker, 1999; Romanos et al., 1992), one can envision screening for epigenetic interactions with well-conserved candidate human disease genes and promoters (Perocchi et al., 2008; Steinmetz et al., 2002) positioned at loci encompassing a wide array of epigenetic states. "
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    ABSTRACT: Classic "position-effect" experiments repositioned genes near telomeres to demonstrate that the epigenetic landscape can dramatically alter gene expression. Here, we show that systematic gene knockout collections provide an exceptional resource for interrogating position effects, not only near telomeres but at every genetic locus. Because a single reporter gene replaces each deleted gene, interrogating this reporter provides a sensitive probe into different chromatin environments while controlling for genetic context. Using this approach, we find that, whereas systematic replacement of yeast genes with the kanMX marker does not perturb the chromatin landscape, chromatin differences associated with gene position account for 35% of kanMX activity. We observe distinct chromatin influences, including a Set2/Rpd3-mediated antagonistic interaction between histone H3 lysine 36 trimethylation and the Rap1 transcriptional activation site in kanMX. This interaction explains why some yeast genes have been resistant to deletion and allows successful generation of these deletion strains through the use of a modified transformation procedure. These findings demonstrate that chromatin regulation is not governed by a uniform "histone code" but by specific interactions between chromatin and genetic factors.
    Cell Reports 01/2013; 301(1). DOI:10.1016/j.celrep.2012.12.003 · 8.36 Impact Factor
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