Chronic Intermittent Hypoxia Promotes Epigenetic Regulation of Inflammatory Gene Promoters in Microglia

Abstract

Microglial inflammatory activities contribute to chronic neuroinflammation and cognitive impairments in virtually all CNS disorders. Chronic intermittent hypoxia (CIH), a hallmark of sleep disordered breathing, causes significant hippocampal and cortical neuron loss and subsequent cognitive decline and impaired vigilance. Previously, we demonstrated an upregulation of microglial pro-inflammatory activities early in CIH neuropathology in rodent models. CIH also increased the expression of the Jumonji C family histone demethylase, JMJD3, in microglia in vitro and in vivo. The expression correlated with reduced global histone H3K27 tri-methylation levels, suggesting the potential for increased gene transcription during CIH in immortalized microglia. Therefore, we tested the hypothesis that epigenetic regulation at pro-inflammatory gene promoters contributes to microglial inflammatory activity following early CIH exposure. We used ChIP qPCR to detect JMJD3 binding patterns, in addition to H3K27 tri-methylation patterns, at inflammatory gene promoters in immortalized N9 microglia exposed to 21% O2 (normoxia) or 10 min cycles of 21% O2 and 1% O2 (CIH). Preliminary results demonstrate that CIH increases JMJD3 binding at the inflammatory genes interleukin-6 and cyclooxygenase-2 compared to normoxia. We further show high H3K27 trimethylation at inflammatory genes in normoxic samples, consistent with minimal inflammatory gene transcription in the healthy CNS. These studies are the first to investigate the effects of histone modifying enzymes during CIH in any cell type, and to suggest a mechanistic underpinning for CIH-induced neuroinflammation. Supported by NIH R01HL111598.