Regulation Of Histone 3 Acetylation By Intermittent Hypoxia

Acetylation of nucleosome core histone proteins determines the structure of chromatin, which regulates the accessibility of DNA sequences to the transcriptional machinery. In general, histone hyperacetylation activates gene transcription and histone hypoacetylation leads to gene silencing. Intermittent hypoxia (IH), a hallmark feature of sleep apnea, induces transcriptional activation of several genes. Whether histone acetylation contributes to IH‐induced gene transcription is not known. The goal of the present study was to determine the effects of IH on histone acetylation and assess the underlying mechanisms. Experiments were performed on rat pheochromocytoma (PC12) cells exposed to alternating cycles of 1.5% O 2 for 30 sec followed by 20% O 2 for 5 min. Exposure of cells to 60 cycles of IH increased global acetylation of histone 3 (H3) but not histone 4 (H4) in a stimulus‐dependent and reversible manner compared to cell exposed to normoxia (20% O 2 ). Specific lysine residues K9, K14, K18 and K27 contributed to increased H3 acetylation by IH. Histone deacetylase (HDAC) inhibitors mimicked IH‐increased H3 acetylation under normoxic conditions. IH reduced HDAC3 and HDAC5 protein expression. Pharmacological blockade of NADPH oxidase with triazolo pyrimidine (VAS‐2870), a specific Nox inhibitor inhibited the increased H3 acetylation and decreased HDAC expression that were induced by IH. These results suggest that ROS generated by NADPH oxidase triggers IH‐induced HDAC downregulation, leading to increased H3 acetylation. Support or Funding Information Supported by NIH‐PO1‐HL90554.