Miller, Dana LFawcett, Emily Marie2015-09-292015-09-292015Fawcett_washington_0250E_14977.pdfhttp://hdl.handle.net/1773/34061Thesis (Ph.D.)--University of Washington, 2015Fluctuations in environmental conditions can be deadly. The ability to rapidly and appropriately respond to stressful conditions can mean the difference between life and death. The toxic gas hydrogen sulfide (H2S) is a common workplace toxin that, at low doses, can protect against hypoxic damage in mammals and extend lifespan in nematodes. However, the enduring implications of exposure to H2S are largely unknown. In my dissertation research, I discovered that the response to H2S in the nematode C. elegans results in long-term and stable changes to cellular physiology that helps protect the animal in an ever-changing environment. Utilizing a new method that we developed for reliable and reproducible delivery of gases at defined concentrations, I discovered that H2S protects against hypoxia-induced disruption of proteostasis. Excitingly, treatment with H2S after hypoxic injury was still effective in reestablishing proteostasis, highlighting new potential for H2S as a therapy after ischemia reperfusion injuries. One strategy that animals use to survive in a changing environment is to predict the onset and pre-emptively respond to stressful conditions based on prior life experiences. There is emerging evidence that this strategy, known as cellular bookmarking, is established through changes to the epigenetic landscape. I discovered that the response to low levels of H2S forms a cellular bookmark that is maintained through development and protects against otherwise lethal doses of H2S later in life. A network of histone modifiers and chromatin remodeling complexes are required for the maintenance of a bookmark of H2S. In the future, these two uniquely tractable models can be leveraged to define mechanisms that allow animals to code changes of environmental conditions into chromatin modifications in a tightly controlled manner. I propose that these coded changes will help to explain, at least partially, differences in sensitivity between individuals to drugs, stress, and even aging.application/pdfen-USCopyright is held by the individual authors.bookmark; C. elegans; epigenetics; H3K4me; hydrogen sulfide; SWI/SNFCellular biologyBiochemistryMolecular biologymolecular and cellular biologyThesis