Discovery and functional characterization of the hypoxia-responsive methyllysine proteome

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For many organisms, survival is dependent upon adapting to environmental variability in temperature, oxygen, and water supply. Among these stresses, survival of most metazoans is inherently tied to the availability of oxygen, such that mechanisms have evolved to survive severe reductions in the environment. In humans, oxygen restriction is most commonly encountered at high altitudes, during development, and in many clinical conditions such as stroke, hypertension, ischemic heart disease, and acute myocardial infarction. During periods of cell stress, the reversible post translational modification (PTM) of proteins provide cells with the ability to rapidly modify their cellular environment and regulate protein function in response to various stimuli. Recent research exploring the role of post translational lysine (Lys) methylation has shown that dynamic methylation functions in a similar manner to other PTMs, as a means to rapidly regulate protein function and biological processes. Several pathways involved in low oxygen sensing and organismal survival, including HIF-1 (hypoxia-inducible factor-1), the unfolded protein response, as well as NFkb and PI3K-Akt signaling pathways have been recently documented to undergo reversible regulation by Lys methylation, however the link between methylation-induced regulation of these pathways under low oxygen stress have not yet been explored. Although studies have recently established that Lys methylation is a prevalent PTM with diverse functional roles, we have only just begun to delineate the extent of the methyllysine proteome and the full spectrum of cellular and developmental processes that it can regulate. To date, methylation research has been primarily focused on the discovery of Lys methylated protein and modification sites, with little knowledge of its biological consequence. My research expertise in low oxygen biology, paired with my postdoctoral research in functional proteomics and Lys methylation discovery, place my research effort in an unprecedented position to advance the basic understanding of how protein methylation regulates survival in low oxygen environments. My lab will focus on bringing together comparative stress biology, functional proteomics, and bioinformatics to discover and assign biological significance to post translational Lys methylation in the fundamental regulation of pathways and signaling networks that enable cells to survive hypoxia (1% O2). My research contributions will not only empower our basic understanding of low oxygen stress response, protein methylation, and function, but will also discover how Lys methylated proteins contribute and coordinate the response to one of the most fundamental and life-threatening stresses to humans oxygen limitation.