Mechanisms of hydrogen-sulfide effects on the epigenetic landscape

University Of Washington, Seattle WA

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Abstract

ABSTRACT 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.