Since histone demethylases and other chromatin-remodeling enzymes are known to play a role in the development of addiction, ethanol-related phenotypes have been characterized for the 13 Jumonji (JmjC) domain-containing histone demethylase genes in Drosophila. For 5 of the genes loss-of-function mutations result in atypical alcohol response phenotypes: JHDM2 (ortholog of 4 human genes, including KDM3A, KDM3B and JMJD1C), Kdm5 (ortholog of 4 human KDM5 genes), NO66 (ortholog of human RIOX1 and RIOX2), HSPBAP1 (ortholog of human HSPBAP1), and JMJD7 (ortholog of human JMJD7).
None of the orthologous human genes has been introduced into flies.
Phenotypes observed for loss-of-function mutations of the 5 Drosophila genes involve various combinations of changes in sensitivity and tolerance: increased sensitivity and reduced tolerance (JHDM2), increased sensitivity and normal tolerance (NO66), increased sensitivity and increased tolerance (Kdm5), normal or slightly reduced sensitivity and reduced tolerance (HSPBAP1 and JMJD7). Targeted knockdown in the nervous system effected by pan-neuronal RNAi was performed for JHDM2, Kdm5, and NO66; phenotypes similar to those for loss-of-function mutations were observed.
[updated Jul. 2018 by FlyBase; FBrf0222196]
Alcoholism can be defined as persistence of excessive drinking over a long period of time despite adverse health effects and disruption of social relations (Morozova et al., 2014; pubmed:24395673).
The 2013 Diagnostic and Statistical Manual of Mental Disorders (DSM) combined the two former categorizations of abnormal alcohol use (alcohol abuse and alcohol dependence) into one diagnosis: alcohol use disorder. The severity of an individual's AUD is broken into classifications: mild, moderate, or severe. "Alcoholism" is a non-medical term often used to describe a severe form of alcohol use disorder. (https://www.therecoveryvillage.com/recovery-blog/alcoholism-alcohol-use-disorder-whats-difference/)
Excessive alcohol consumption is associated with increased risk of different types of cancer, higher cardiovascular disease mortality, birth defects, liver diseases, and neuropsychiatric disorders (Morozova et al., 2014; pubmed:24395673).
Histone demethylases play key roles in regulation of gene expression via chromatin remodeling and epigenetic changes. The largest class of histone demethylase enzymes contain a Jumonji C (JmjC) domain and catalyse lysine demethylation of histones through an oxidative reaction that requires iron Fe(II) and α-ketoglutarate as cofactors. The JmjC-domain-containing histone demethylases (JHDMs) can remove all three histone lysine-methylation states. (Klose et al., 2006; pubmed:16983801)
Moderate-scoring ortholog of human KDM3A, KDM3B, JMJD1C, and HR (1 Drosophila to 4 human). Dmel\JHDM2 shares 33-41% identity and 49-53% similarity with KDM3A, KDM3B, and JMJD1C; it is less closely related to HR.