HDAC and p300/CBP activities regulate Reactive Oxygen species dependent increase in Histone 3 acetylation in response to intermittent hypoxia

Histone3 (H3) lysine acetylation levels regulate transcriptional activation through a dynamic process involving equilibrium between histone acetylases (KATs) and histone deacetylases (KDACs). We have previously shown that lysine acetylation of H3 is an early epigenetic mechanism associated with Hypoxia inducible transcription factor (HIF-1) activation and sympathetic excitation in rodent models of intermittent hypoxia (IH), a hallmark feature of sleep apnea (Wang et al, Front Physiol 2021). The goal of the present study was to determine the molecular mechanisms underlying IH increased H3 acetylation. We tested the hypothesis that IH decreased KDAC activity leads to increased KAT activity, thereby increasing H3 acetylation. Pheochromocytoma (PC)-12 cells exposed to IH (1.5% O2 for 30 sec followed by 20% O2 for 5 min) exhibited reduced KDAC and increased KAT enzyme activity along with increased global acetylation of H3 in a stimulus-dependent and reversible manner. Increased H3 acetylation by IH was blocked by an antioxidant. Conversely, reactive oxygen species (ROS) mimetics, like IH, increased H3 acetylated protein expression. Treating cells with Trichostatin A (TSA), an inhibitor of KDACs mimicked IH-increased H3 acetylation under normoxic conditions. Pharmacological blockade p300/CBP (KAT) with CTK7A abolished IH-induced increased H3 acetylation. Similar to PC12 cells, decreased KDAC activity lead to augmented p300/CBP mediated H3 acetylation in both rats exposed to IH and heme-oxygnease null mice (HO-2-/-) which exhibit high incidence of apneas. In summary, interplay between KATs and KDACs regulate ROS-dependent H3 acetylation and the ensuing IH induced transcriptional activity leading to sympathetic activation. NIH-PO1-HL90554 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.