Exposure to environmental toxins can elicit epigenetic changes with the long-term effect to modulate transcription, leading to long-lasting effects that alter disease susceptibility, drug efficacy, and even the rate of aging. The mechanisms by which environmental conditions are translated into changes in the epigenetic landscape are poorly understood. We have discovered a new epigenetic transcriptional memory in response to H2S exposure in C. elegans. H2S is a common environmental toxin, and is the second most common cause of occupational deaths from inhaled gas, behind only carbon monoxide. In this project, we will leverage the power of C. elegans genetics to test the hypothesis that environmental toxins such as H2S alter the epigenetic landscape. We will measure transcriptional responses associated with specific H2S exposures that have differential phenotypic effects, and delineate how epigenetic effects associated with the response to H2S alters transcriptional response to subsequent toxin exposure. Our preliminary data show that the conserved ATP- dependent chromatin-remodeling enzyme SWI/SNF is required for the long-lasting memory of H2S. We will measure the genomic localization of SWI/SNF components and determine when and where the complex is required to test the hypothesis that chromatin remodeling underlies the transcriptional memory of H2S. Finally, we have isolated new mutations that disrupt the normal epigenetic response to H2S. We will use the power of C. elegans molecular and genetic biology to identify the genes and pathways that mediate the long- lasting effects of H2S exposure. Together, these studies will reveal fundamental features of how cellular responses integrate with epigenetic factors to coordinate long-term effects environmental stimuli in animals. Moreover, this project will facilitate career enhancement and mentoring that will fully integrate the PI?s lab with the excellent environmental health science community at the University of Washington.
The proposed research is relevant to public health because it will advance our understanding of how environmental toxins have long-term effects on basic physiology. The environment can have important affects on disease susceptibility, drug efficacy, and even aging. Therefore, a basic molecular understanding of the how these changes are initiated could have wide-ranging clinical applications. We are using the powerful molecular genetic model organism C. elegans, which we have found develops a memory of exposure to the environmental toxin hydrogen sulfide. Sulfide is a common environmental and occupational toxin that humans are exposed to. Therefore, by understanding how sulfide has these long-lasting effects in C. elegans, we will learn about how the environment changes gene expression as well as suggest new strategies for treating the people exposed to sulfide.
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|Horsman, Joseph W; Miller, Dana L (2016) Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide. J Biol Chem 291:5320-5|
|Leiser, Scott F; Miller, Hillary; Rossner, Ryan et al. (2015) Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. Science 350:1375-1378|