This report describes characterization of the fly alcohol response using the Drosophila gene nej. Dmel\nej encodes an acetyltransferase that acetylates several nuclear proteins, including histones, providing a tag for transcriptional activation; it is orthologous to two paralogous CREB-binding protein (CBP) genes in human, CREBBP and EP300. Both human genes are implicated in human syndromic diseases (see MIM:600140 and MIM:602700). Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\nej.
Neither human gene, CREBBP or EP300, has been introduced into flies.
Animals heterozygous for an amorphic mutation of Dmel\nej develop normally, but adults exhibit a significantly reduced capacity to develop alcohol tolerance (alcohol-induced increase in alcohol resistance). A large number of genetic and physical interactions have been described for Dmel\nej; see below and in the nej gene report.
It is postulated that mutations in nej impair alcohol-induced acetylation of transcriptional control regions for a number of alcohol-response genes, including slo (see FBhh0000683). Normally, expression of these genes is increased upon exposure to alcohol; in heterozygous nej mutant animals, this response is not observed.
[updated Oct. 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).
Alcoholism is a multifactorial, genetically influenced disorder. [from MIM:103780; 2017.12.19]
CREBBP encodes an acetyltransferase that acetylates histones, giving a specific tag for transcriptional activation, as well as some non-histone proteins. The CREBBP protein binds specifically to phosphorylated CREB transcription factor and enhances its transcriptional activity toward cAMP-responsive genes. [Gene Cards, CREBBP; 2018.10.23]
EP300 and CREBBP are paralogous genes. [Gene Cards, EP300; 2018.10.23]
The EP300 protein functions as a histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB transcription factor. [Gene Cards, EP300; 2018.10.23]
Many to one: 2 human to 1 Drosophila. The human genes are EP300 and CREBBP.
Many to one: 2 human to 1 Drosophila. The human genes are EP300 and CREBBP.
Moderate- to high-scoring ortholog of human EP300 and CREBBP. Dmel\nej shares 35% identity and 43% similarity with the human genes.
