Epigenetic Mechanisms Regulating Chronic Intermittent Hypoxia-evoked Sympathetic Activation

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Project Summary- Project 4 The overall goal of the Project 4 is to assess the epigenetic mechanisms underlying sympathetic activation caused by intermittent hypoxia (IH), a major manifestation of sleep apnea. Histone modification by lysine acetylation is a major epigenetic mechanism. Lysine acetylation is determined by equilibrium between histone acetyltransferases (HATs) and histone deacetylases (HDACs). Preliminary data showed that: a) IH inhibits HDAC activity with little or no effect on HAT activity, b) IH induces lysine acetylation of histone (H)-3, c) lysine acetylation is an early epigenetic mechanism initiated by IH, and d) Inhibiting HDAC activity results in HIF-1- stabilization and transcription. Based on the preliminary data, Project 4 tests the hypothesis that IH-evoked HIF-1 transcriptional activation requires lysine acetylation of the HIF-1α protein and histone-3, which in turn activates DNA methyl transferases leading to DNA methylation and long-lasting sympathetic activation. This hypothesis will be tested in rat pheochromocytoma (PC)-12 cell cultures, intact rats exposed IH, and in mice exhibiting spontaneous sleep apnea and uses molecular, biochemical and physiological approaches. Studies in Aim1 assess how IH inhibits HDAC activity. Experiments in Aim2 determine how decreased HDAC activity by IH activates HIF-1-mediated transcription. Aim 3 determines the consequences of HIF-1 activation by lysine acetylation on IH-evoked sympathetic activation. Aim 4 determines whether lysine acetylation by short-term IH leads to DNA methylation by long-term IH. Major conceptual and technical innovations of the Project 4 are: a) the hypothesis that lysine acetylation by short-term IH drives the long-term IH-induced DNA methylation is conceptually novel, and provides new mechanistic molecular insights into the progression of autonomic dysfunction in the context of sleep apnea from a reversible to a non-reversible phenotype, and b) assessing the significance of findings from experimental rodent model of IH in mice exhibiting natural sleep apnea. Project 4 has tight thematic linkages with Projects 1, 2, 3, and 4 and utilizes Core B facilities for exposing rodents and cell cultures to IH. Investigative team consists of molecular biologists, epigenesists, and physiologists who have long-standing experience and expertise with the proposed approaches and a track record of working together for number years as evidenced by joint publications. Successful completion of the Project 4 is anticipated to provide much needed molecular basis for progression of disease from a reversible to non-reversible phenotype, wherein currently no information is available.