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General Information
Name
alcohol, response to, JmjC-domain-containing genes
FlyBase ID
FBhh0000846
OMIM
Overview

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), lid (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 (lid), 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, lid, and NO66; phenotypes similar to those for loss-of-function mutations were observed.

[updated Jul. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: alcohol use disorder, susceptibility to (fly models overview)
Symptoms and phenotype
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 OMIM:103780; 2017.12.19]
Specific Disease Summary: alcohol, response to, JmjC-domain-containing genes
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Histone demethylases and other chromatin-remodeling enzymes are known to play a role in the development of addiction (FBrf0237320 and references cited therein).
Genetics
Cellular phenotype and pathology
Molecular information
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)
External links
    Disease synonyms
    AUD susceptibility, JmjC-domain-containing genes
    alcohol use disorder, susceptibility to (postulated), JmjC-domain-containing genes
    Search term: histone demethylase
    Search term: JHDM
    Search term: alcohol, response to, epigenetic mechanisms
    Ortholog Information
    Human gene(s) in FlyBase
      Other mammalian ortholog(s) used
        D. melanogaster Gene Information (5)
        Gene Snapshot
        JmjC domain-containing histone demethylase 2 (JHDM2) encodes an enzyme that catalyzes the removal of methyl groups from the lysine 9 of the product of His3, and thereby promotes an open chromatin structure. [Date last reviewed: 2019-03-07]
        Cellular component (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)
        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.
        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Gene Snapshot
        little imaginal discs (lid) encodes a trimethyl H3K4 histone demethylase that regulates transcription through both demethylase-dependent and demethylase-independent mechanisms. It has roles in regulating cell growth, circadian rhythm, stress resistance, hematopoiesis and fertility. [Date last reviewed: 2019-03-14]
        Gene Groups / Pathways
        Comments on ortholog(s)
        Moderate- to high-scoring ortholog of human KDM5A, KDM5B, KDM5C, and KDM5D (1 Drosophila to 4 human). Dmel\lid shares 39-42% identity and 53-57% similarity with the human genes.
        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Gene Snapshot
        In progress.Contributions welcome.
        Cellular component (GO)
        Gene Groups / Pathways
        Comments on ortholog(s)
        Moderate- to high-scoring ortholog of human RIOX1 and RIOX2 (1 Drosophila to 2 human). Dmel\NO66 shares 27-35% identity and 44-51% similarity with the human genes.
        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Gene Snapshot
        Insufficient genetic data for FlyBase to solicit a summary. [Date last reviewed: 2016-06-30]
        Cellular component (GO)
        Gene Groups / Pathways
          Comments on ortholog(s)
          Moderate- to high-scoring ortholog of human HSPBAP1 (1 Drosophila to 1 human). Dmel\HSPBAP1 shares 31% identity and 46% similarity with the human gene.
          Orthologs and Alignments from DRSC
          DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
          Gene Snapshot
          Insufficient genetic data for FlyBase to solicit a summary. [Date last reviewed: 2016-06-30]
          Cellular component (GO)
          Gene Groups / Pathways
          Comments on ortholog(s)
          High-scoring ortholog of human JMJD7 (1 Drosophila to 1 human). Dmel\JMJD7 shares 44% identity and 62% similarity with the human gene.
          Orthologs and Alignments from DRSC
          DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
          Synthetic Gene(s) Used (0)
          Summary of Physical Interactions (31 groups)
          protein-protein
          Interacting group
          Assay
          References
          bimolecular fluorescence complementation, fluorescence microscopy
          anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry
          anti bait coimmunoprecipitation, western blot
          ion exchange chromatography, molecular sieving, affinity chromatography technology, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
          anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
          ion exchange chromatography, molecular sieving, affinity chromatography technology, Identification by mass spectrometry
          anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, anti tag coimmunoprecipitation
          molecular sieving, western blot, anti bait coimmunoprecipitation, affinity chromatography technology, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, Identification by mass spectrometry, ion exchange chromatography
          enzymatic study, peptide massfingerprinting, pull down, molecular weight estimation by staining
          anti bait coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, western blot, anti tag coimmunoprecipitation, ion exchange chromatography, affinity chromatography technology
          pull down, autoradiography, anti bait coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry
          anti tag coimmunoprecipitation, peptide massfingerprinting, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot
          anti bait coimmunoprecipitation, western blot, pull down, autoradiography
          bimolecular fluorescence complementation, fluorescence microscopy
          protein-protein
          Interacting group
          Assay
          References
          anti tag coimmunoprecipitation, anti tag western blot, western blot
          protein-protein
          Interacting group
          Assay
          References
          experimental knowledge based
          experimental knowledge based
          experimental knowledge based
          experimental knowledge based
          experimental knowledge based
          experimental knowledge based
          experimental knowledge based
          Alleles Reported to Model Human Disease (Disease Ontology) (3 alleles)
          Models Based on Experimental Evidence ( 2 )
          Modifiers Based on Experimental Evidence ( 1 )
          Allele
          Disease
          Interaction
          References
          Genetic Tools, Stocks and Reagents
          Sources of Stocks
          Contact lab of origin for a reagent not available from a public stock center.
          Bloomington Stock Center Disease Page
          Selected mammalian transgenes
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila transgenes
          Allele
          Transgene
          Publicly Available Stocks
          RNAi constructs available
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila classical alleles
          Allele
          Allele class
          Mutagen
          Publicly Available Stocks
          amorphic allele - molecular evidence
          I-SceI
          amorphic allele - molecular evidence
          Delta2-3 transposase
          amorphic allele - molecular evidence
          I-SceI
          amorphic allele - molecular evidence
          CRISPR/Cas9
          amorphic allele - molecular evidence
          I-SceI
          References (4)