title: Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain.
abstract: Single nucleotide polymorphism (rs1997794) in promoter of the prodynorphin gene (PDYN) associated with alcohol-dependence may impact PDYN transcription in human brain. To address this hypothesis we analyzed PDYN mRNA levels in the dorsolateral prefrontal cortex (dl-PFC) and hippocampus, both involved in cognitive control of addictive behavior and PDYN promoter SNP genotype in alcohol-dependent and control human subjects. The principal component analysis suggested that PDYN expression in the dl-PFC may be related to alcoholism, while in the hippocampus may depend on the genotype. We also demonstrated that the T, low risk SNP allele resides within noncanonical AP-1-binding element that may be targeted by JUND and FOSB proteins, the dominant AP-1 constituents in the human brain. The T to C transition abrogated AP-1 binding. The impact of genetic variations on PDYN transcription may be relevant for diverse adaptive responses of this gene to alcohol.
authors.affiliation: Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden. mumtaz.malik@farmbio.uu.se
authors.forename: Malik Mumtaz
authors.initials: MM
authors.lastname: Taqi
authors.forename: Igor
authors.initials: I
authors.lastname: Bazov
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yakovleva
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D005838:Genotype; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; D018808:Transcription Factor AP-1; C033660:preproenkephalin