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Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2011 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1385, 18-25 p.Article in journal (Refereed) Published
Abstract [en]

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 FOSS 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.

Place, publisher, year, edition, pages
2011. Vol. 1385, 18-25 p.
Keyword [en]
Alcohol dependence, Endogenous opioid system, Prodynorphin, Gene polymorphism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-151563DOI: 10.1016/j.brainres.2011.02.042ISI: 000289810800003PubMedID: 21338584OAI: oai:DiVA.org:uu-151563DiVA: diva2:410428
Available from: 2011-04-13 Created: 2011-04-13 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Mechanisms of Prodynorphin Gene Dysregulation in the Brain of Human Alcoholics
Open this publication in new window or tab >>Mechanisms of Prodynorphin Gene Dysregulation in the Brain of Human Alcoholics
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The endogenous opioid system (EOS) including dynorphin opioid peptides and κ-opioid receptor (KOR) plays a critical role in alcohol dependence. Aims of the thesis were to evaluate whether the EOS undergoes molecular adaptations in brain areas involved in cognitive control of addiction in human alcohol dependent subjects, and to analyze the impact of genetic and epigenetic factors on these adaptive changes. The main findings were that (1) the dynorphin/KOR system including PDYN mRNA and dynorphins in the dorsolateral prefrontal cortex (dl-PFC), dynorphins in the hippocampus, and KOR mRNA in the orbitofrontal cortex (OFC), is upregulated in human alcoholics. No other significant changes in the EOS were found. (2) Three PDYN single nucleotide polymorphisms (SNPs), which show the most significant association with alcohol dependence, form CpG sites that are methylated in human brain at different levels. Methylation of the C, non-risk variant of the 3’-untranslated region (3’-UTR) SNP (rs2235749; C>T) was increased in dl-PFC and positively correlated with dynorphins. The DNA-binding factor that differentially targeted the T, risk allele and methylated and unmethylated C allele of this SNP was identified in human brain. We hypothesize that influences of the genetic, epigenetic and environmental factors may be integrated through alterations in methylation of the PDYN 3’jUTR CpG/SNP and, as a consequence, affect PDYN transcription and vulnerability to develop alcohol dependence. (3) 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 of the PDYN promoter SNP (rs1997794; T>C). The T, low risk allele of this SNP resides within non-canonical AP-1-binding element and 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. (4) It was proposed that PDYN transcription may be regulated by intragenic DNA regulatory elements controlling the DNA-protein interactions through formation of non-canonical DNA secondary structures. The dynorphin-encoding sequence in PDYN was found to have potential to form such DNA structure in vitro, and this formation was affected by CpG methylation in this region. This methylation sensitive non-canonical DNA structure formation may be involved in regulation of initiation of PDYN transcription from alternative start sites located within this region, or in splicing of non-canonical mRNA.

In conclusion, the dynorphin/KOR system has been identified as the site of robust adaptive changes associated with alcohol dependence in the areas of human brain involved in cognitive control of addiction. Regulation of PDYN was found to be brain area specific, apparently affected by the genetic and epigenetic factors, and possibly dependent on the internal properties of the gene such as its ability to form non-canonical DNA secondary structures.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 147
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-158235 (URN)978-91-554-8149-0 (ISBN)
Public defence
2011-10-14, BMC, B7:101, Husargatan3, Uppsala University, Sweden, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-09-22 Created: 2011-09-02 Last updated: 2012-05-11Bibliographically approved
2. Epigenetic Dysregulations in the Brain of Human Alcoholics: Analysis of Opioid Genes
Open this publication in new window or tab >>Epigenetic Dysregulations in the Brain of Human Alcoholics: Analysis of Opioid Genes
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuropeptides are special in their expression profiles restricted to neuronal subpopulations and low tissue mRNA levels. Genetic, epigenetic and transcriptional mechanisms that define spatiotemporal expression of the neuropeptide genes have utmost importance for the formation and functions of neural circuits in normal and pathological human brain. This thesis focuses on regulation of transcription of the opioid/nociceptin genes, the largest neuropeptide family, and on identification of adaptive changes in these mechanisms associated with alcoholism as model human pathology. Two epigenetic mechanisms, the common for most cells in the dorsolateral prefrontal cortex (dlPFC) and the neuron-subpopulation specific that may orchestrate prodynorphin (PDYN) transcription in the human dlPFC have been uncovered. The first, repressive mechanism may operate through control of DNA methylation/demethylation in a short, nucleosome size promoter CpG island (CGI). The second mechanism may involve USF2, the sequence–specific methylation–sensitive transcription factor which interaction with its target element in the CpG island results in USF2 and PDYN co-expression in the same neurons. The short PDYN promoter CGI may function as a chromatin element that integrates cellular and environmental signals through changes in methylation and transcription factor binding. Alterations in USF2–dependent PDYN transcription are affected by the promoter SNP (rs1997794: T>C) under transition to pathological state, i.e. in the alcoholic brain. This and two other PDYN SNPs that are most significantly associated with alcoholism represent CpG-SNPs, which are differentially methylated in the human dlPFC. The T, low risk allele of the promoter SNP forms a noncanonical AP-1–binding element. JUND and FOSB proteins, which may form homo- or heterodimers have been identified as dominant constituents of AP-1 complex. The C, non-risk variant of the PDYN 3′ UTR SNP (rs2235749 SNP: C>T) demonstrated significantly higher methylation in alcoholics compared to controls. PDYN mRNA and dynorphin levels significantly and positively correlated with methylation of the PDYN 3′ UTR CpG-SNP suggesting its involvement in PDYN regulation. A DNA–binding factor with differential binding affinity for the T allele and methylated and unmethylated C alleles of the PDYN 3′ UTR SNP (the T allele specific binding factor, Ta-BF) has been discovered, which may function as a regulator of PDYN transcription. These findings emphasize the complexity of PDYN regulation that determines its expression in specific neuronal subpopulations and suggest previously unknown integration of epigenetic, transcriptional and genetic mechanisms that orchestrate alcohol–induced molecular adaptations in the human brain. Given the important role of PDYN in addictive behavior, the findings provide a new insight into fundamental molecular mechanisms of human brain disorder. In addition to PDYN in the dlPFC, the PNOC gene in the hippocampus and OPRL1 gene in central amygdala that were downregulated in alcoholics may contribute to impairment of cognitive control over alcohol seeking and taking behaviour.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 84 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 209
Keyword
neuropeptides, dynorphin, human brain, alcohol dependence, epigenetics, gene transcription
National Category
Natural Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-270321 (URN)978-91-554-9445-2 (ISBN)
Public defence
2016-02-26, B/B7:113a, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-02-04 Created: 2015-12-27 Last updated: 2016-02-12

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Taqi, Malik MumtazBazov, IgorWatanabe, HiroyukiYakovleva, TatjanaBakalkin, Georgy

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