Project 2: Functional profiling of susceptibility genes
Summary
Presentation: Overview of Project 2
Humans vary in their genetic susceptibility to the toxic effects of chemicals found at Superfund sites. Cancers and other forms of toxicity may arise from adverse gene-environment interactions. Genetic susceptibility to the toxic effects of a chemical is likely to be related to the cellular targets of the chemical and its metabolites. However, we still have a limited understanding of cellular targets for many of the priority chemicals on the Superfund list. Project investigators are taking advantage of the conservation of basic metabolic pathways and fundamental cellular processes between the yeast S. cerevisiae and humans to identify candidate human susceptibility genes. They are using a new approach to discover these targets in yeast and human cells using parallel deletion analysis (PDA) and RNA interference (RNAi), respectively. Deletion strains for almost every yeast gene enable new approaches to determine in parallel (PDA) the relative importance of each yeast gene for susceptibility (sensitivity) to a chemical toxicant. They are endeavoring to identify candidate susceptibility genes for selected priority Superfund chemicals that require metabolic activation including benzene, polycyclic aromatic hydrocarbons (PAHs), halogenated aliphatic hydrocarbons, and for selected metals such as arsenic and cadmium, which do not. Project investigators select and prioritize likely human candidate genes by computational analysis of the yeast data sets. The candidate human susceptibility genes are silenced in appropriate human cell lines using RNAi so that their roles in sensitivity to cytotoxicity, genotoxicity and epigenetic effects of the Superfund chemical and/or its metabolites can be evaluated. The investigators believe that this approach will identify genes that confer human susceptibility to Superfund chemicals and their metabolites and will enable future work to examine associations between variants in these genes and adverse outcomes. In addition, this work will likely provide important insights in the cellular processes leading to toxicity for priority Superfund chemicals.
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Project Update
Many people are exposed to a variety of toxic chemicals present in the environment on a daily basis. However, only some people develop disease (get sick) as a result. An individual’s chances depend in part on subtle differences in the genes which comprise the genetic blueprint for each person. Unfortunately, for most toxic chemicals, researchers don’t know where to look for these important variations because they don’t know which of the tens of thousands of genes are important for dealing with each toxic chemical. In this project, Drs. Christopher Vulpe and Luoping Zhang are figuring out which genes are the important ones to focus on by using baker’s yeast. By using yeast, they have been able to check thousands of genes for their importance in an individual’s vulnerability to Superfund chemicals. In the past year, the research group led by Dr. Chris Vulpe found several genes associated with the packaging of DNA in a cell (the chromatin) as key to sensitivity to arsenic. Dr. Luoping Zhang’s group further demonstrated the importance of one of these genes in human cells. Arsenic is an established cause of bladder cancer in humans and these findings suggest that alterations in the way that DNA is packaged into chromatin may affect arsenic’s toxicity and carcinogenicity. In the next year, the group plans to look to see if these variations in these genes play a role in the likelihood that a person will develop bladder cancer or other diseases after being exposed to arsenic. Understanding the genetic determinants of chemical susceptibility in humans can help identify groups of people that could be at increased risk of developing disease following exposure to toxic agents, and to design prevention and intervention strategies with the aim of preserving public health.
Publications
- Zhang L, Freeman LE, Nakamura J, Hecht SS, Vandenberg JJ, Smith MT, Sonawane BR (2009) Formaldehyde and leukemia: Epidemiology, potential mechanisms, and implications for risk assessment. /Environ Mol Mutagen/. Sep 29. [Epub ahead of print]. PMID: 19790261. [Abstract]
- Hosgood HD 3rd, Zhang L, Shen M, Berndt SI, Vermeulen R, Li G, Yin S, Yeager M, Yuenger J, Rothman N, Chanock S, *Smith M*, Lan Q (2009) Association between genetic variants in VEGF, ERCC3 and occupational benzene hematotoxicity. /Occup Environ Med/. Sep 22. [Epub ahead of print]. PMID: 19773279 [Abstract]
- Jo WJ, Loguinov A, Wintz H, Chang M, Smith AH, Kalman D, Zhang L, Smith MT, Vulpe CD (2009) Comparative Functional Genomic Analysis Identifies Distinct and Overlapping Sets of Genes Required for Resistance to Monomethylarsonous Acid (MMAIII) and Arsenite (AsIII) in Yeast. Toxicol Sci. 111(2), 424-436. PMID: 19635755. PMCID: PMC274584. [Abstract] [Full text]
- Jo, William J., Jeung H. Kim, Eric Oh, Daniel Jaramillo, Patricia Holman, Alex V. Loguinov, Adam Arkin, Corey Nislow, Guri Giaever, and Christopher Vulpe. 2009. Novel Insights Into iron metabolism by integrating deletome and transcriptome analysis in an iron deficiency model ofthe yeast Saccharomyces cerevisiae. Genomics. 10(130):doi:10.1186/1471-2164-10-130 (http://dx.doi.org/10.1186/1471-2164-10-130)
- Lan, Qing, Luoping Zhang, Min Shen, William J. Jo, Roel Vermeulen, Guilan Li, Christopher Vulpe, Sophia Lim, Xuefeng Ren, Stephen M. Rappaport, Sonja I. Berndt, Meredith Yeager, Jeff Yuenger, Richard B. Hayes, Martha S. Linet, Songnian Yin, Stephen Chanock, Martyn T. Smith, and Nathaniel Rothman. 2009. Large-scale evaluation of candidate genes Identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity. Carcinogenesis. (http://carcin.oupjournals.org/) 30(1):50-58. doi:10.1093/carcin/bgn249 (http://dx.doi.org/10.1093/carcin/bgn249)
- Ren, Xuefeng, Sophia Lim, Martyn T. Smith, and Luoping Zhang. 2009. Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicological Sciences. (http://www3.oup.co.uk/toxsci/) 107(2):367-75. doi:10.1016/j.taap.2008.11.017 (http://dx.doi.org/10.1016/j.taap.2008.11.017)
- Scelo, Ghislaine, Catherine Metayer, L. Zhang, Joseph L. Wiemels, Melinda C. Aldrich, Steve Selvin, Stacy Month, M.T. Smith, and Patricia A. Buffler. 2009. Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia. Environmental Health Perspectives. 117(1):133-9. doi:10.1289/ehp.11927 (http://dx.doi.org/10.1289/ehp.11927)