Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways

Abstract

Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could underlie transcriptomic and behavioral hallmarks of alcohol addiction. In the present study, we sought to identify epigenetic enzymes in the brain that are dysregulated during protracted abstinence as a consequence of chronic and intermittent alcohol exposure. Through quantitative mRNA expression analysis of over 100 epigenetic enzymes, we identified 11 that are significantly altered in alcohol-dependent rats compared with controls. Follow-up studies of one of these enzymes, the histone demethylase KDM6B, showed that this enzyme exhibits region-specific dysregulation in the prefrontal cortex and nucleus accumbens of alcohol-dependent rats. KDM6B was also upregulated in the human alcoholic brain. Upregulation of KDM6B protein in alcohol-dependent rats was accompanied by a decrease of trimethylation levels at histone H3, lysine 27 (H3K27me3), consistent with the known demethylase specificity of KDM6B. Subsequent epigenetic (chromatin immunoprecipitation [ChIP]-sequencing) analysis showed that alcohol-induced changes in H3K27me3 were significantly enriched at genes in the IL-6 signaling pathway, consistent with the well-characterized role of KDM6B in modulation of inflammatory responses. Knockdown of KDM6B in cultured microglial cells diminished IL-6 induction in response to an inflammatory stimulus. Our findings implicate a novel

Histone Methylation Regulation in Neurodegenerative Disorders

“…H3K27me3 was enhanced via recruitment of EZH2 at the BDNF and ARC loci in the amygdala of the alcoholic postmortem brain, with the corresponding decrease in Arc and BDNF expression in the early-onset AUD postmortem brain amygdala [ 181 ]. Consistent with the above observations, increased KDM6B, which regulates H3K27me3 levels, was found in individuals with AUD in the anterior cingulate cortex [ 182 ]. These limited studies pinpoint the participation of both H3K4me3 and H3K27me3 marks’ mediated gene regulation in human AUD’s pathophysiology.…”

RETRACTED: H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation

“… 25 The highly expressed KDM6B was observed in the alcoholic brain of rats, while the KDM6B knockdown resulted in repressed inflammation in microglial cells through the inhibition of IL-6 induction. 26 Hence KDM6B silencing has a significant protective role against ischemic brain injury through its ability to alleviate neurological deficits and suppress inflammation.…”

Factors associated with fluoxetine and norfluoxetine plasma concentrations and clinical response in Mexican patients with mental disorders

“…In the study of Domingues and cols in 2016, 13 tor role of ethanol is widely recognized 26,27 ; previous studies have shown that humans with constant alcohol use exhibit chronic alterations in gene expressions. 28 Furthermore, this disorder has been related with higher aldosterone concentrations, 29 and this hormone plays a key regulator role in maintaining blood pressure and the body fluid balance through the electrolyte homeostasis. 30,31 The effects of high aldosterone concentrations include an increase in urinary excretion, 32 which can be responsible for the higher fluoxetine clearance, and its consequent lower concentration.…”