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Zhong, Quan

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Zhong

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Quan

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Zhong, Quan
Author's Publications: search.filters.isAuthorOfPublication.4cf322e8-eeca-47f5-9cfb-40ab9a5368c9

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    Edgetic Perturbation Models of Human Inherited Disorders
    (Nature Publishing Group, 2009) Simonis, Nicolas; Li, Qian-Ru; Heuze, Fabien; Klitgord, Niels; Tam, Stanley; Venkatesan, Kavitha; Mou, Danny; Swearingen, Venus; Yildirim, Muhammed; Dricot, Amélie; Szeto, David; Lin, Chenwei; Hao, Tong; Fan, Changyu; Milstein, Stuart; Dupuy, Denis; Brasseur, Robert; Zhong, Quan; Charloteaux, Benoit; Yu, Haiyuan; Yan, Han; Hill, David; Cusick, Michael; Vidal, Marc
    Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as ‘nodes' and ‘edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products (‘node removal') and interaction-specific or edge-specific (‘edgetic') alterations. Global computational analyses of ~50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies.
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    A Yeast Model of FUS/TLS-Dependent Cytotoxicity
    (Public Library of Science, 2011) Ju, Shulin; Tardiff, Daniel F.; Han, Haesun; Divya, Kanneganti; Maquat, Lynne E.; Bosco, Daryl A.; Hayward, Lawrence J.; Lindquist, Susan; Weissman, Jonathan S.; Zhong, Quan; Brown, Robert H.; Ringe, Dagmar; Petsko, Gregory
    FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/ RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.