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Zhou H, Gelernter J. Human genetics and epigenetics of alcohol use disorder. J Clin Invest 2024; 134:e172885. [PMID: 39145449 PMCID: PMC11324314 DOI: 10.1172/jci172885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024] Open
Abstract
Alcohol use disorder (AUD) is a prominent contributor to global morbidity and mortality. Its complex etiology involves genetics, epigenetics, and environmental factors. We review progress in understanding the genetics and epigenetics of AUD, summarizing the key findings. Advancements in technology over the decades have elevated research from early candidate gene studies to present-day genome-wide scans, unveiling numerous genetic and epigenetic risk factors for AUD. The latest GWAS on more than one million participants identified more than 100 genetic variants, and the largest epigenome-wide association studies (EWAS) in blood and brain samples have revealed tissue-specific epigenetic changes. Downstream analyses revealed enriched pathways, genetic correlations with other traits, transcriptome-wide association in brain tissues, and drug-gene interactions for AUD. We also discuss limitations and future directions, including increasing the power of GWAS and EWAS studies as well as expanding the diversity of populations included in these analyses. Larger samples, novel technologies, and analytic approaches are essential; these include whole-genome sequencing, multiomics, single-cell sequencing, spatial transcriptomics, deep-learning prediction of variant function, and integrated methods for disease risk prediction.
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Affiliation(s)
- Hang Zhou
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
- Department of Biomedical Informatics and Data Science
- Center for Brain and Mind Health
| | - Joel Gelernter
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
- Department of Genetics, and
- Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA
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Yang B, Zhang R, Leong Bin Abdullah MFI. The association between neuropsychiatric effects of substance use and occurrence of endoplasmic reticulum and unfolded protein response: A systematic review. Toxicol Lett 2024; 391:71-85. [PMID: 38101493 DOI: 10.1016/j.toxlet.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/01/2023] [Accepted: 12/11/2023] [Indexed: 12/17/2023]
Abstract
INTRODUCTION This systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR) through comprehensive electronic search of existing literature and review of their findings. METHODS A comprehensive electronic literature search was carried out on research articles published between 1950 to July 2023 through major databases, such as Scopus, Web of Science, Google Scholar, PubMed, PsycINFO, EMBASE, Medline and Cochrane Library. RESULTS A total of 21 research articles were selected for review, which were comprised of sixteen animal studies, four human studies and one study on postmortem human brain samples. The selected studies revealed that alcohol, methamphetamine, cocaine, opioid and kratom exposures contributed to neuropsychiatric effects: such as decline in learning and memory function, executive dysfunction, alcohol, methamphetamine, opioid, and kratom dependence. These effects were associated with activation and persistent of ER stress and UPR with elevation of BiP and CHOP expression and the direction of ER stress is progressing towards the PERK-eIF2α-ATF4-CHOP pathway and neuronal apoptosis and neurodegeneration at various regions of the brain. In addition, regular kratom use in humans also contributed to elevation of p-JNK expression, denoting progress of ER stress towards the IRE1-ASK1-JNK-p-JNK pathway which was linked to kratom use disorder. However, treatment with certain compounds or biological agents could reverse the activation of ER stress. CONCLUSIONS The neuropsychiatric effects of alcohol, methamphetamine, cocaine, opioid and kratom use may be associated with persistent ER stress and UPR.
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Affiliation(s)
- Bin Yang
- Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, SAINS@BERTAM, Kepala Batas, Pulau Pinang, Malaysia; 2nd Affiliated Hospital, Xinxiang Medical University, Henan, China
| | - Ruiling Zhang
- 2nd Affiliated Hospital, Xinxiang Medical University, Henan, China
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Ghemrawi M, Tejero NF, Duncan G, McCord B. Pyrosequencing: Current forensic methodology and future applications-a review. Electrophoresis 2023; 44:298-312. [PMID: 36168852 DOI: 10.1002/elps.202200177] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 02/01/2023]
Abstract
The recent development of small, single-amplicon-based benchtop systems for pyrosequencing has opened up a host of novel procedures for applications in forensic science. Pyrosequencing is a sequencing by synthesis technique, based on chemiluminescent inorganic pyrophosphate detection. This review explains the pyrosequencing workflow and illustrates the step-by-step chemistry, followed by a description of the assay design and factors to keep in mind for an exemplary assay. Existing and potential forensic applications are highlighted using this technology. Current applications include identifying species, identifying bodily fluids, and determining smoking status. We also review progress in potential applications for the future, including research on distinguishing monozygotic twins, detecting alcohol and drug abuse, and other phenotypic characteristics such as diet and body mass index. Overall, the versatility of the pyrosequencing technologies renders it a useful tool in forensic genomics.
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Affiliation(s)
- Mirna Ghemrawi
- Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA
| | - Nicole Fernandez Tejero
- Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA
| | - George Duncan
- Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Dania Beach, Florida, USA
| | - Bruce McCord
- Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA
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Han X, Liu T, Zhai J, Liu C, Wang W, Nie C, Wang Q, Zhu X, Zhou H, Tian W. Association between EPHA5 methylation status in peripheral blood leukocytes and the risk and prognosis of gastric cancer. PeerJ 2022; 10:e13774. [PMID: 36164608 PMCID: PMC9508887 DOI: 10.7717/peerj.13774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/01/2022] [Indexed: 01/19/2023] Open
Abstract
Purpose Altered DNA methylation, genetic alterations, and environmental factors are involved in tumorigenesis. As a tumor suppressor gene, abnormal EPHA5 methylation was found in gastric cancer (GC) tissues and was linked to the initiation, progression and prognosis of GC. In this study, the EPHA5 methylation level in peripheral blood leukocytes (PBLs) was detected to explore its relationship with GC risk and prognosis. Methods A total of 366 GC cases and 374 controls were selected as the subjects of this study to collect their environmental factors, and the EPHA5 methylation status was detected through the methylation-sensitive high-resolution melting method. Logistic regression analysis was utilized to evaluate the associations among EPHA5 methylation, environmental factors and GC risk. Meanwhile, the propensity score (PS) was used to adjust the imbalance of some independent variables. Results After PS adjustment, EPHA5 Pm (positive methylation) was more likely to increase the GC risk than EPHA5 Nm (negative methylation) (ORb = 1.827, 95% CI [1.202-2.777], P = 0.005). EPHA5 Pm had a more significant association with GC risk in the elderly (ORa = 2.785, 95% CI [1.563-4.961], P = 0.001) and H. pylori-negative groups (ORa = 2.758, 95% CI [1.369-5.555], P = 0.005). Moreover, the combined effects of EPHA5 Pm and H. pylori infection (ORc a = 3.543, 95% CI [2.233-5.621], P < 0.001), consumption of alcohol (ORc a = 2.893, 95% CI [1.844-4.539], P < 0.001), and salty food intake (ORc a = 4.018, 95% CI [2.538-6.362], P < 0.001) on increasing the GC risk were observed. In addition, no convincing association was found between EPHA5 Pm and the GC prognosis. Conclusions EPHA5 methylation in PBLs and its combined effects with environmental risk factors are related to the GC risk.
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Nazari S, Pourmand SM, Makki SM, Brand S, Vousooghi N. Potential biomarkers of addiction identified by real-time PCR in human peripheral blood lymphocytes: a narrative review. Biomark Med 2022; 16:739-758. [PMID: 35658670 DOI: 10.2217/bmm-2021-0291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Addiction-related neurobiological factors could be considered as potential biomarkers. The concentration of peripheral biomarkers in tissues like blood lymphocytes may mirror their brain levels. This review is focused on the mRNA expression of potential addiction biomarkers in human peripheral blood lymphocytes (PBLs). PubMed, EMBASE, Web of Science, Scopus and Google Scholar were searched using the keywords 'addiction', 'biomarker', 'peripheral blood lymphocyte', 'gene expression' and 'real-time PCR'. The results showed the alterations in the regulation of genes such as dopamine receptors, opioid receptors, NMDA receptors, cannabinoid receptors, α-synuclein, DYN, MAO-A, FosB and orexin-A as PBLs biomarkers in addiction stages. Such variations could also be found during abstinence and relapse. PBLs biomarkers may help in drug development and have clinical implications.
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Affiliation(s)
- Shahrzad Nazari
- Department of Neuroscience & Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran
| | - Seyed Mahmoud Pourmand
- Addiction Department, School of Behavioral Sciences & Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, 1445613111, Iran
| | - Seyed Mohammad Makki
- Department of Psychiatry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Serge Brand
- Center for Affective-, Stress- and Sleep Disorders (ZASS), Psychiatric Clinics (UPK), University of Basel, Basel, 4002, Switzerland.,Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Department of Sport, Exercise, and Health, Division of Sport Science and Psychosocial Health, University of Basel, Basel, 4052, Switzerland.,Department of Psychiatry, School of Medicine, Tehran University of Medical Sciences, Tehran, 1417466191, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran.,Research Center for Cognitive & Behavioral Sciences, Tehran University of Medical Sciences, Tehran, 13337159140, Iran.,Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, 1336616357, Iran
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Veerappa A, Pendyala G, Guda C. A systems omics-based approach to decode substance use disorders and neuroadaptations. Neurosci Biobehav Rev 2021; 130:61-80. [PMID: 34411560 PMCID: PMC8511293 DOI: 10.1016/j.neubiorev.2021.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/23/2021] [Accepted: 08/14/2021] [Indexed: 11/15/2022]
Abstract
Substance use disorders (SUDs) are a group of neuropsychiatric conditions manifesting due to excessive dependence on potential drugs of abuse such as psychostimulants, opioids including prescription opioids, alcohol, inhalants, etc. Experimental studies have generated enormous data in the area of SUDs, but outcomes from such data have remained largely fragmented. In this review, we attempt to coalesce these data points providing an important first step towards our understanding of the etiology of SUDs. We propose and describe a 'core addictome' pathway that behaves central to all SUDs. Besides, we also have made some notable observations paving way for several hypotheses; MECP2 behaves as a master switch during substance use; five distinct gene clusters were identified based on respective substance addiction; a central cluster of genes serves as a hub of the addiction pathway connecting all other substance addiction clusters. In addition to describing these findings, we have emphasized the importance of some candidate genes that are of substantial interest for further investigation and serve as high-value targets for translational efforts.
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Affiliation(s)
- Avinash Veerappa
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Gurudutt Pendyala
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Center for Biomedical Informatics Research and Innovation, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Ramamoorthy K, Sabui S, Srinivasan P, Al-Juburi S, Pham Q, Chu BD, Simoes RD, Fleckenstein JM, Said HM. Effect of chronic alcohol exposure on gut vitamin B7 uptake: involvement of epigenetic mechanisms and effect of alcohol metabolites. Am J Physiol Gastrointest Liver Physiol 2021; 321:G123-G133. [PMID: 34077272 PMCID: PMC8410103 DOI: 10.1152/ajpgi.00144.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Vitamin B7 (biotin) is essential for normal health and its deficiency/suboptimal levels occur in a variety of conditions including chronic alcoholism. Mammals, including humans, obtain biotin from diet and gut-microbiota via absorption along the intestinal tract. The absorption process is carrier mediated and involves the sodium-dependent multivitamin transporter (SMVT; SLC5A6). We have previously shown that chronic alcohol exposure significantly inhibits intestinal/colonic biotin uptake via suppression of Slc5a6 transcription in animal and cell line models. However, little is known about the transcriptional/epigenetic factors that mediate this suppression. In addition, the effect of alcohol metabolites (generated via alcohol metabolism by gut microbiota and host tissues) on biotin uptake is still unknown. To address these questions, we first demonstrated that chronic alcohol exposure inhibits small intestinal and colonic biotin uptake and SMVT expression in human differentiated enteroid and colonoid monolayers. We then showed that chronic alcohol exposures of both, Caco-2 cells and mice, are associated with a significant suppression in expression of the nuclear factor KLF-4 (needed for Slc5a6 promoter activity), as well as with epigenetic alterations (histone modifications). We also found that chronic exposure of NCM460 human colonic epithelial cells as well as human differentiated colonoid monolayers, to alcohol metabolites (acetaldehyde, ethyl palmitate, ethyl oleate) significantly inhibited biotin uptake and SMVT expression. These findings shed light onto the molecular/epigenetic mechanisms that mediate the inhibitory effect of chronic alcohol exposure on intestinal biotin uptake. They further show that alcohol metabolites are also capable of inhibiting biotin uptake in the gut.NEW & NOTEWORTHY Using complementary models, including human differentiated enteroid and colonoid monolayers, this study shows the involvement of molecular and epigenetic mechanisms in mediating the inhibitory effect of chronic alcohol exposure on biotin uptake along the intestinal tract. The study also shows that alcohol metabolites (generated by gut microbiota and host tissues) cause inhibition in gut biotin uptake.
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Affiliation(s)
- Kalidas Ramamoorthy
- 1Department of Physiology/Biophysics, University of California, Irvine, California
| | - Subrata Sabui
- 1Department of Physiology/Biophysics, University of California, Irvine, California,5Veterans Affairs Medical Center, Long Beach, California
| | - Padmanabhan Srinivasan
- 1Department of Physiology/Biophysics, University of California, Irvine, California,5Veterans Affairs Medical Center, Long Beach, California
| | - Saleh Al-Juburi
- 1Department of Physiology/Biophysics, University of California, Irvine, California
| | - Quang Pham
- 1Department of Physiology/Biophysics, University of California, Irvine, California
| | - Brian D. Chu
- 1Department of Physiology/Biophysics, University of California, Irvine, California,5Veterans Affairs Medical Center, Long Beach, California
| | - Rita D. Simoes
- 3Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri
| | - James M. Fleckenstein
- 3Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri,4Veterans Affairs Medical Center, St. Louis Missouri
| | - Hamid M. Said
- 1Department of Physiology/Biophysics, University of California, Irvine, California,2Department of Medicine, University of California, Irvine, California,5Veterans Affairs Medical Center, Long Beach, California
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Siomek-Gorecka A, Dlugosz A, Czarnecki D. The Molecular Basis of Alcohol Use Disorder (AUD). Genetics, Epigenetics, and Nutrition in AUD: An Amazing Triangle. Int J Mol Sci 2021; 22:ijms22084262. [PMID: 33924016 PMCID: PMC8072802 DOI: 10.3390/ijms22084262] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022] Open
Abstract
Alcohol use disorder (AUD) is a very common and complex disease, as alcohol is the most widely used addictive drug in the world. This disorder has an enormous impact on public health and social and private life, and it generates a huge number of social costs. Alcohol use stimulates hypothalamic-pituitary-adrenal (HPA) axis responses and is the cause of many physical and social problems (especially liver disease and cancer), accidental injury, and risky sexual behavior. For years, researchers have been trying to identify the genetic basis of alcohol use disorder, the molecular mechanisms responsible for its development, and an effective form of therapy. Genetic and environmental factors are known to contribute to the development of AUD, and the expression of genes is a complicated process that depends on epigenetic modulations. Dietary nutrients, such as vitamins, may serve as one these modulators, as they have a direct impact on epigenomes. In this review, we connect gathered knowledge from three emerging fields-genetics, epigenetics, and nutrition-to form an amazing triangle relating to alcohol use disorder.
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Affiliation(s)
- Agnieszka Siomek-Gorecka
- Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-095 Bydgoszcz, Poland
- Correspondence: ; Tel.: +48-52-585-37-48
| | - Anna Dlugosz
- Department of Engineering and Chemical and Food Analytics, Faculty of Chemical Technology and Engineering, UTP University of Science and Technology, 85-326 Bydgoszcz, Poland;
| | - Damian Czarnecki
- Department of Preventive Nursing, Faculty of Health Sciences, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-821 Bydgoszcz, Poland;
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Sandoval-Sierra JV, Salgado García FI, Brooks JH, Derefinko KJ, Mozhui K. Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter. Clin Epigenetics 2020; 12:76. [PMID: 32493461 PMCID: PMC7268244 DOI: 10.1186/s13148-020-00868-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 05/19/2020] [Indexed: 12/14/2022] Open
Abstract
Background A long-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here, we examine whether we can detect DNA methylation changes associated with a few days’ use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics. Results The perioperative methylome underwent significant changes over the three visits that were primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was a significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5–210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: < 25 MME, 25–90 MME, and ≥ 90 MME. Using mixed-effects modeling, 4 CpGs had significant positive associations with opioid dose at two-tailed p value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, one-tailed p value = 0.02) and duration of opioid use (regression coefficient = 0.003, one-tailed p value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene, RASL10A, that may be predictive of opioid dosage. Conclusion The present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use and that epigenetic differences in OPRM1 and other sites are associated with a short-term use of therapeutic opioids.
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Affiliation(s)
- Jose Vladimir Sandoval-Sierra
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Francisco I Salgado García
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jeffrey H Brooks
- Department of Oral and Maxillofacial Surgery, College of Dentistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Karen J Derefinko
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Khyobeni Mozhui
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
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Maier HB, Neyazi M, Neyazi A, Hillemacher T, Pathak H, Rhein M, Bleich S, Goltseker K, Sadot-Sogrin Y, Even-Chen O, Frieling H, Barak S. Alcohol consumption alters Gdnf promoter methylation and expression in rats. J Psychiatr Res 2020; 121:1-9. [PMID: 31710958 DOI: 10.1016/j.jpsychires.2019.10.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/07/2019] [Accepted: 10/28/2019] [Indexed: 11/17/2022]
Abstract
Alcohol use disorder is one of the most disabling diseases worldwide. Glial-cell derived neurotrophic factor (Gdnf) shows promising results concerning the inhibition of alcohol consumption in rodent models. We investigated the epigenetic regulation of Gdnf following ethanol consumption and withdrawal in a rat model. 32 Wistar rats underwent 7 weeks of intermittent access to alcohol in a 2-bottle choice (IA2BC). Whole blood, Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) were collected immediately after the last 24 h of an alcohol-drinking session (alcohol group, AG) or 24 h after withdrawal (withdrawal group, WG). MRNA levels were measured using real-time quantitative PCR. Bisulfite-conversion of DNA and capillary sequencing was used to determine methylation levels of the core promoter (CP) and the negative regulatory element (NRE). The CP of the AG in the NAc was significantly less methylated compared to controls (p < 0.05). In the NAc, mRNA expression was significantly higher in the WG (p < 0.05). In the WG, mRNA expression levels in the VTA were significantly lower (p < 0.05) and showed significantly less methylation in the NRE in the VTA (p < 0.001) and the NAc (p < 0.01) compared to controls. Changes in the cerebral mRNA expression correspond to alterations in DNA methylation of the Gdnf promoter in a rodent model. Our results hold clinical relevance since differences in Gdnf mRNA expression and DNA methylation could be a target for pharmacological interventions.
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Affiliation(s)
- Hannah Benedictine Maier
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany.
| | - Meraj Neyazi
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Alexandra Neyazi
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Thomas Hillemacher
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany; Department of Psychiatry and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany
| | - Hansi Pathak
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Mathias Rhein
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Stefan Bleich
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Koral Goltseker
- School of Psychological Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Yossi Sadot-Sogrin
- School of Psychological Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Oren Even-Chen
- School of Psychological Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Helge Frieling
- Department of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Segev Barak
- School of Psychological Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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Mitra A, Chatterjee S, Gupta DK. Environmental Arsenic Exposure and Human Health Risk. ADVANCES IN WATER SECURITY 2020. [DOI: 10.1007/978-3-030-21258-2_5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Zhang Y, Li Y, Luo L, He Q, Gao Y, Feng H, Zhao L, Wei W, Fu S, Sun D. Factors Affecting Differential Methylation of DNA Promoters in Arsenic-Exposed Populations. Biol Trace Elem Res 2019; 189:437-446. [PMID: 30220071 DOI: 10.1007/s12011-018-1504-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/30/2018] [Indexed: 01/15/2023]
Abstract
The exposure/biotransformation of inorganic arsenic (iAs) may perturb DNA methylation patterns and subsequently influence disease risk by altering the expression of key genes. Interindividual variation in patterns of DNA methylation can be explained by the influence of environmental, genetic, and stochastic factors. Here, we examined promoter DNA methylation levels with urinary arsenical concentrations and investigated the genetic and nongenetic determinants of DNA methylation in 105 samples collected from populations in Shanxi Province, China, with high levels of arsenic in drinking water. Arsenic concentrations in water were determined by atomic absorption spectrophotometry (AA-6800, Shimadzu Co., Kyoto, Japan). Urine samples were measured using an atomic absorption spectrophotometer with an arsenic speciation pretreatment system (ASA-2sp, Shimadzu Co. Kyoto, Japan) for detection. Gene-specific (CDH1, EREG, ERCC2, GSTP1, and MGMT) DNA methylation was quantified by targeted bisulfite sequencing. Single-nucleotide polymorphism (SNP) genotyping was performed using a custom-by-design 2 × 48-Plex SNPscan™ Kit. These results revealed CDH1 with promoter DNA methylation levels associated with iAs. After the exclusion of confounding factors, age was correlated with increased methylation of the CDH1 gene. The susceptibility of the CDH1 and GSTP1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs2424932) GA genotype, and the susceptibility of the CDH1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs6087990) TC genotype. Although the above results must still be replicated in larger samples, the findings improve our understanding of the pathogenesis of arsenic and may highlight certain DNA methylation markers as attractive surrogate markers for prevention research.
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Affiliation(s)
- Yanting Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Yuanyuan Li
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Lanrong Luo
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Qian He
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Yanhui Gao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Hongqi Feng
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Lijun Zhao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Wei Wei
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China
| | - Songbo Fu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China.
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China.
| | - Dianjun Sun
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China.
- Key Lab of Etiology and Epidemiology, Education Bureau of Hei Long Jiang Province & Ministry of Health, Harbin, 150081, China.
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13
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Mahna D, Puri S, Sharma S. DNA methylation signatures: Biomarkers of drug and alcohol abuse. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 777:19-28. [DOI: 10.1016/j.mrrev.2018.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/22/2018] [Accepted: 06/18/2018] [Indexed: 01/08/2023]
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Lax E, Szyf M. The Role of DNA Methylation in Drug Addiction: Implications for Diagnostic and Therapeutics. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 157:93-104. [PMID: 29933958 DOI: 10.1016/bs.pmbts.2018.01.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Drug addiction is a devastating health problem that is a very heavy burden on the individual affected and the society in general. Recent research defines addiction as a neurobehavioral disorder. Underpinning biological mechanisms of drug addiction are abnormal neuronal and brain activity following acute and repeated drug exposure. Abnormal gene expression is found in reward and decision-making brain regions of addicts and in animal models and is possibly responsible for changes in brain function. DNA methylation is an epigenetic modification that regulates gene expression. Global and site-specific changes in DNA methylation are observed in addiction. Here, we discuss recent findings on the involvement of DNA methylation in drug addiction from animal and human studies. We also propose future directions for utilizing DNA methylation-based approaches for diagnosis, therapeutics, and evaluation of response to therapy in drug addiction.
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Affiliation(s)
- Elad Lax
- Department of Pharmacology and Therapeutics, McGill University Medical School, Montreal, QC, Canada
| | - Moshe Szyf
- Department of Pharmacology and Therapeutics, McGill University Medical School, Montreal, QC, Canada.
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15
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Liu C, Jiao C, Wang K, Yuan N. DNA Methylation and Psychiatric Disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 157:175-232. [PMID: 29933950 DOI: 10.1016/bs.pmbts.2018.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
DNA methylation has been an important area of research in the study of molecular mechanism to psychiatric disorders. Recent evidence has suggested that abnormalities in global methylation, methylation of genes, and pathways could play a role in the etiology of many forms of mental illness. In this article, we review the mechanisms of DNA methylation, including the genetic and environmental factors affecting methylation changes. We report and discuss major findings regarding DNA methylation in psychiatric patients, both within the context of global methylation studies and gene-specific methylation studies. Finally, we discuss issues surrounding data quality improvement, the limitations of current methylation analysis methods, and the possibility of using DNA methylation-based treatment for psychiatric disorders in the future.
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Affiliation(s)
- Chunyu Liu
- University of Illinois, Chicago, IL, United States; School of Life Science, Central South University, Changsha, China.
| | - Chuan Jiao
- School of Life Science, Central South University, Changsha, China
| | - Kangli Wang
- School of Life Science, Central South University, Changsha, China
| | - Ning Yuan
- Hunan Brain Hospital, Changsha, China
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16
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Glahn A, Rhein M, Heberlein A, Muschler M, Kornhuber J, Frieling H, Bleich S, Hillemacher T. The Epigenetic Regulation of GATA4-Dependent Brain Natriuretic Peptide Expression during Alcohol Withdrawal. Neuropsychobiology 2018; 74:131-138. [PMID: 28441648 DOI: 10.1159/000456011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 12/20/2016] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Natriuretic peptides participate in the collection of metabolic effects during alcohol withdrawal. Having witnessed modulation of other natriuretic peptides in alcohol-dependent patients during alcohol withdrawal, we were interested in the relation of brain natriuretic peptide (BNP) methylation with protein expression and craving in this longitudinal study. METHODS Ninety-nine male patients were compared to 101 healthy controls concerning epigenetic regulation and protein expression during detoxification treatment. RESULTS With BNP expression being GATA4 dependent, we observed a correlation of GATA4 binding site methylation and protein expression. BNP serum levels and Obsessive Compulsive Drinking Scale scores are significantly decreased during withdrawal. Focusing on the two CpGs that are between GATA transcription factor binding sites, statistical analysis revealed a reversely proportional methylation pattern, significantly increasing with ongoing detoxification and thereby supporting the observed serum level changes. CONCLUSION Without the functional knowledge about regulation of BNP expression via the GATA transcription factor, it would have been easy to take the mean results of the global CpG data and propose a direct relationship between methylation and expression. Thus, these findings are a voice for functionally and mechanistically approved results. There was no causal relationship between protein expression levels and epigenetic changes. Further research is needed which includes protein expression and other approaches.
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Affiliation(s)
- Alexander Glahn
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
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17
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Savarese AM, Lasek AW. Transcriptional Regulators as Targets for Alcohol Pharmacotherapies. Handb Exp Pharmacol 2018; 248:505-533. [PMID: 29594350 PMCID: PMC6242703 DOI: 10.1007/164_2018_101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Alcohol use disorder (AUD) is a chronic relapsing brain disease that currently afflicts over 15 million adults in the United States. Despite its prevalence, there are only three FDA-approved medications for AUD treatment, all of which show limited efficacy. Because of their ability to alter expression of a large number of genes, often with great cell-type and brain-region specificity, transcription factors and epigenetic modifiers serve as promising new targets for the development of AUD treatments aimed at the neural circuitry that underlies chronic alcohol abuse. In this chapter, we will discuss transcriptional regulators that can be targeted pharmacologically and have shown some efficacy in attenuating alcohol consumption when targeted. Specifically, the transcription factors cyclic AMP-responsive element binding protein (CREB), peroxisome proliferator-activated receptors (PPARs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and glucocorticoid receptor (GR), as well as the epigenetic enzymes, the DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), will be discussed.
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Affiliation(s)
| | - Amy W. Lasek
- Department of Psychiatry, University of Illinois at Chicago,Corresponding author: 1601 West Taylor Street, MC 912, Chicago, IL 60612, Tel: (312) 355-1593,
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18
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Prom-Wormley EC, Ebejer J, Dick DM, Bowers MS. The genetic epidemiology of substance use disorder: A review. Drug Alcohol Depend 2017; 180:241-259. [PMID: 28938182 PMCID: PMC5911369 DOI: 10.1016/j.drugalcdep.2017.06.040] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 06/20/2017] [Accepted: 06/23/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Substance use disorder (SUD) remains a significant public health issue. A greater understanding of how genes and environment interact to regulate phenotypes comprising SUD will facilitate directed treatments and prevention. METHODS The literature studying the neurobiological correlates of SUD with a focus on the genetic and environmental influences underlying these mechanisms was reviewed. Results from twin/family, human genetic association, gene-environment interaction, epigenetic literature, phenome-wide association studies are summarized for alcohol, nicotine, cannabinoids, cocaine, and opioids. RESULTS There are substantial genetic influences on SUD that are expected to influence multiple neurotransmission pathways, and these influences are particularly important within the dopaminergic system. Genetic influences involved in other aspects of SUD etiology including drug processing and metabolism are also identified. Studies of gene-environment interaction emphasize the importance of environmental context in SUD. Epigenetic studies indicate drug-specific changes in gene expression as well as differences in gene expression related to the use of multiple substances. Further, gene expression is expected to differ by stage of SUD such as substance initiation versus chronic substance use. While a substantial literature has developed for alcohol and nicotine use disorders, there is comparatively less information for other commonly abused substances. CONCLUSIONS A better understanding of genetically-mediated mechanisms involved in the neurobiology of SUD provides increased opportunity to develop behavioral and biologically based treatment and prevention of SUD.
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Affiliation(s)
- Elizabeth C Prom-Wormley
- Dvision of Epidemiology, Department of Family Medicine and Population Health, Virginia Commonwealth University, PO Box 980212, Richmond, VA 23298-0212, USA.
| | - Jane Ebejer
- School of Cognitive Behavioural and Social Sciences, University of New England, Armidale, NSW 2350, Australia
| | - Danielle M Dick
- Department of Psychology, Virginia Commonwealth University, PO Box 842509, Richmond, VA 23284-2509, USA
| | - M Scott Bowers
- Faulk Center for Molecular Therapeutics, Biomedical Engeneering, Northwestern University, Evanston, IL 60201, USA
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19
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Philibert R, Glatt SJ. Optimizing the chances of success in the search for epigenetic biomarkers: Embracing genetic variation. Am J Med Genet B Neuropsychiatr Genet 2017; 174:589-594. [PMID: 28696057 PMCID: PMC5562041 DOI: 10.1002/ajmg.b.32569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 06/16/2017] [Indexed: 01/21/2023]
Abstract
The emphasis on clinical translation in biomedical research continues to grow. This focus has been particularly notable in those investigators using epigenetic approaches to decipher the biology of complex behavioral disorders. As a result of these efforts, reproducible findings for several disorders, such as smoking, have been generated, giving rise to hopes that biomarkers for other behavioral illnesses would be forthcoming. Unfortunately, that biomedical cornucopia has not yet materialized. In this editorial, we review progress to date and discuss barriers to generating epigenetic biomarkers for complex behavioral disorders. We highlight the need to incorporate information on genetic variation and develop more powerful bioinformatics tools in order to optimize the likelihood of success. We emphasize that searches should focus on clearly defined, readily distinguishable behavioral constructs and suggest that some well-intentioned methods, such as correction for cellular heterogeneity, may actually impede the identification of clinically relevant biomarkers in peripheral blood. Finally, we describe how the understanding created by the development of these biomarkers may lead to more valid animal models of neuropsychiatric illness. We conclude that the prospects for epigenetic biomarkers for complex disorders are bright, but emphasize that the journey to the clinical implementation of these findings will be a slow, iterative process.
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Affiliation(s)
- Robert Philibert
- Behavioral Diagnostics, Coralville, Iowa
- Department of Psychiatry, University of Iowa, Iowa City, Iowa
| | - Stephen J Glatt
- Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York
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20
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Marie-Claire C, Jourdaine C, Lépine JP, Bellivier F, Bloch V, Vorspan F. Pharmacoepigenomics of opiates and methadone maintenance treatment: current data and perspectives. Pharmacogenomics 2017; 18:1359-1372. [DOI: 10.2217/pgs-2017-0040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Current treatments of opioid addiction include primarily maintenance medications such as methadone. Chronic exposure to opiate and/or long-lasting maintenance treatment induce modulations of gene expression in brain and peripheral tissues. There is increasing evidence that epigenetic modifications underlie these modulations. This review summarizes published results on opioid-induced epigenetic changes in animal models and in patients. The epigenetic modifications observed with other drugs of abuse often used by opiate abusers are also outlined. Specific methadone maintenance treatment induced epigenetic modifications at different treatment stages may be combined with the ones resulting from patients’ substance use history. Therefore, research comparing groups of addicts with similar history and substances use disorders but contrasting for well-characterized treatment phenotypes should be encouraged.
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Affiliation(s)
- Cynthia Marie-Claire
- Variabilité de réponse aux psychotropes, INSERMU1144/Faculté de Pharmacie de Paris/Université Paris Descartes/Université ParisDiderot/Université Sorbonne Paris Cité, Paris, France
| | - Clément Jourdaine
- AP-HP, GH Saint-Louis – Lariboisière – F. Widal, Pôle de Psychiatrie et de Médecine Addictologique, 75475 Paris cedex 10, France
| | - Jean-Pierre Lépine
- AP-HP, GH Saint-Louis – Lariboisière – F. Widal, Pôle de Psychiatrie et de Médecine Addictologique, 75475 Paris cedex 10, France
| | - Frank Bellivier
- Variabilité de réponse aux psychotropes, INSERMU1144/Faculté de Pharmacie de Paris/Université Paris Descartes/Université ParisDiderot/Université Sorbonne Paris Cité, Paris, France
- AP-HP, GH Saint-Louis – Lariboisière – F. Widal, Pôle de Psychiatrie et de Médecine Addictologique, 75475 Paris cedex 10, France
| | - Vanessa Bloch
- Variabilité de réponse aux psychotropes, INSERMU1144/Faculté de Pharmacie de Paris/Université Paris Descartes/Université ParisDiderot/Université Sorbonne Paris Cité, Paris, France
| | - Florence Vorspan
- Variabilité de réponse aux psychotropes, INSERMU1144/Faculté de Pharmacie de Paris/Université Paris Descartes/Université ParisDiderot/Université Sorbonne Paris Cité, Paris, France
- AP-HP, GH Saint-Louis – Lariboisière – F. Widal, Pôle de Psychiatrie et de Médecine Addictologique, 75475 Paris cedex 10, France
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21
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Cervera-Juanes R, Wilhelm LJ, Park B, Grant KA, Ferguson B. Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking. Alcohol 2017; 60:103-113. [PMID: 27866807 DOI: 10.1016/j.alcohol.2016.11.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/04/2016] [Accepted: 11/07/2016] [Indexed: 02/06/2023]
Abstract
Alcohol-use disorders encompass a range of drinking levels and behaviors, including low, binge, and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression, and the predicted neural effects in the nucleus accumbens core (NAcc) of male rhesus macaques categorized as "low" or "binge" drinkers, compared to "alcohol-naïve" and "heavy" drinkers based on drinking patterns during a 12-month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol-naïve (AN), low/binge (L/BD), and heavy/very heavy (H/VHD) drinking subjects (n = 24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules, and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to PDE10A and PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However, two other DMRs, linked to the CCBE1 and FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining five DMRs also differentiated L/BDs and ANs. However, H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to FZD5 and PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and that the methylation signatures identify synaptic genes that may play a role in preventing the escalation of alcohol use.
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22
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Berkel TDM, Pandey SC. Emerging Role of Epigenetic Mechanisms in Alcohol Addiction. Alcohol Clin Exp Res 2017; 41:666-680. [PMID: 28111764 DOI: 10.1111/acer.13338] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/09/2017] [Indexed: 12/15/2022]
Abstract
Alcohol use disorder (AUD) is a complex brain disorder with an array of persistent behavioral and neurochemical manifestations. Both genetic and environmental factors are known to contribute to the development of AUD, and recent studies on alcohol exposure and subsequent changes in gene expression suggest the importance of epigenetic mechanisms. In particular, histone modifications and DNA methylation have emerged as important regulators of gene expression and associated phenotypes of AUD. Given the therapeutic potential of epigenetic targets, this review aims to summarize the role of epigenetic regulation in our current understanding of AUD by evaluating known epigenetic signatures of brain regions critical to addictive behaviors in both animal and human studies throughout various stages of AUD. More specifically, the effects of acute and chronic alcohol exposure, tolerance, and postexposure withdrawal on epigenetically induced changes to gene expression and synaptic plasticity within key brain regions and the associated behavioral phenotypes have been discussed. Understanding the contribution of epigenetic regulation to crucial signaling pathways may prove vital for future development of novel biomarkers and treatment agents in ameliorating or preventing AUD.
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Affiliation(s)
- Tiffani D M Berkel
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.,Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Subhash C Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.,Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.,Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois
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23
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Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes. Sci Rep 2017; 7:41816. [PMID: 28165486 PMCID: PMC5292964 DOI: 10.1038/srep41816] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/28/2016] [Indexed: 01/19/2023] Open
Abstract
Altered DNA methylation in addiction-related genes may modify the susceptibility to alcohol or drug dependence (AD or ND). We profiled peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 addiction-related genes in 256 African Americans (AAs) (117 cases with AD-ND codependence and 139 controls) and 196 European Americans (103 cases with AD-ND codependence and 93 controls) using Illumina's GoldenGate DNA methylation array assays. AD-ND codependence-associated DNA methylation changes were analyzed using linear mixed-effects models with consideration of batch effects and covariates age, sex, and ancestry proportions. Seventy CpGs (in 41 genes) showed nominally significant associations (P < 0.05) with AD-ND codependence in both AAs and EAs. One CpG (HTR2B cg27531267) was hypomethylated in AA cases (P = 7.2 × 10-5), while 17 CpGs in 16 genes (including HTR2B cg27531267) were hypermethylated in EA cases (5.6 × 10-9 ≤ P ≤ 9.5 × 10-5). Nevertheless, 13 single nucleotide polymorphisms (SNPs) nearby HTR2B cg27531267 and the interaction of these SNPs and cg27531267 did not show significant effects on AD-ND codependence in either AAs or EAs. Our study demonstrated that DNA methylation changes in addiction-related genes could be potential biomarkers for AD-ND co-dependence. Future studies need to explore whether DNA methylation alterations influence the risk of AD-ND codependence or the other way around.
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24
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Drug Addiction and DNA Modifications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 978:105-125. [DOI: 10.1007/978-3-319-53889-1_6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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25
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Cervera-Juanes R, Wilhelm LJ, Park B, Grant KA, Ferguson B. Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes. Transl Psychiatry 2017; 7:e994. [PMID: 28072409 PMCID: PMC5545731 DOI: 10.1038/tp.2016.266] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 11/09/2016] [Accepted: 11/13/2016] [Indexed: 12/20/2022] Open
Abstract
Alterations in DNA methylation have been associated with alcohol exposure and proposed to contribute to continued alcohol use; however, the molecular mechanisms involved remain obscure. We investigated the escalating effects of alcohol use on DNA methylation, gene expression and predicted neural effects in the nucleus accumbens of rhesus macaques that self-administered 4% alcohol for over 12 months. Using an exploratory approach to identify CpG-rich regions, followed by bisulfite sequencing, the methylation levels of 2.7 million CpGs were compared between seven low-binge drinkers and nine heavy-very heavy drinking subjects. We identified 17 significant differential methylation regions (DMRs), including 14 with methylation levels that were correlated with average daily alcohol consumption. The size of the DMRs ranged from 29 to 158 bp (mean=63.7), included 4-19 CpGs per DMR (mean=8.06) and spanned a range of average methylation values from 5 to 34%. Eight of the DMRs mapped to genes implicated in modulating synaptic plasticity. Six of the synaptic genes have not previously been linked to alcohol use. Validation studies of these eight DMRs using bisulfite amplicon sequencing and an expanded set of 30 subjects confirmed the significant alcohol-dose-associated methylation of the DMRs. Expression analysis of three of the DMR-associated genes, LRP5, GPR39 and JAKMIP1, revealed significant correlations between DMR methylation and whole-gene or alternative transcript expression, supporting a functional role in regulating gene expression. Together, these studies suggest that alcohol-associated synaptic remodeling may be regulated and coordinated at the level of DNA methylation.
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Affiliation(s)
- R Cervera-Juanes
- Department of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - L J Wilhelm
- Department of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - B Park
- Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, USA
| | - K A Grant
- Department of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
| | - B Ferguson
- Department of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA,Department of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. E-mail:
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26
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Kamat PK, Mallonee CJ, George AK, Tyagi SC, Tyagi N. Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism. Alcohol Clin Exp Res 2016; 40:2474-2481. [PMID: 27805256 PMCID: PMC5133158 DOI: 10.1111/acer.13234] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 09/08/2016] [Indexed: 12/20/2022]
Abstract
Alcohol is the most socially accepted addictive drug. Alcohol consumption is associated with some health problems such as neurological, cognitive, behavioral deficits, cancer, heart, and liver disease. Mechanisms of alcohol-induced toxicity are presently not yet clear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with amino acid homocysteine (Hcy), which has been linked with brain neurotoxicity. Elevated Hcy impairs with various physiological mechanisms in the body, especially metabolic pathways. Hcy metabolism is predominantly controlled by epigenetic regulation such as DNA methylation, histone modifications, and acetylation. An alteration in these processes leads to epigenetic modification. Therefore, in this review, we summarize the role of Hcy metabolism abnormalities in alcohol-induced toxicity with epigenetic adaptation and their influences on cerebrovascular pathology.
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Affiliation(s)
- Pradip K Kamat
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
- Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida
| | - Carissa J Mallonee
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Akash K George
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Suresh C Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Neetu Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
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27
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Zhang H, Gelernter J. Review: DNA methylation and alcohol use disorders: Progress and challenges. Am J Addict 2016; 26:502-515. [PMID: 27759945 DOI: 10.1111/ajad.12465] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 09/17/2016] [Accepted: 10/02/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Risk for alcohol use disorders (AUDs) is influenced by gene-environment interactions. Environmental factors can affect gene expression through epigenetic mechanisms such as DNA methylation. This review outlines the findings regarding the association of DNA methylation and AUDs. METHODS We searched PubMed (by April 2016) and identified 29 studies that examined the association of DNA methylation and AUDs. We also evaluated the methods used in these studies. RESULTS Two studies demonstrated elevated global (repetitive element) DNA methylation levels in AUD subjects. Fifteen candidate gene studies showed hypermethylation of promoter regions of six genes (AVP, DNMT3B, HERP, HTR3A, OPRM1, and SNCA) or hypomethylation of the GDAP1 promoter region in AUD subjects. Five genome-wide DNA methylation studies demonstrated widespread DNA methylation changes across the genome in AUD subjects. Six studies showed significant correlations of DNA methylation with gene expression in AUD subjects. Three studies revealed interactive effects of genetic variation and DNA methylation on susceptibility to AUDs. Most studies analyzed AUD-associated DNA methylation changes in the peripheral blood; a few studies examined DNA methylation changes in postmortem brains of AUD subjects. DISCUSSION AND CONCLUSIONS Chronic alcohol consumption may result in DNA methylation changes, leading to neuroadaptations that may underlie some of the mechanisms of AUD risk and persistence. Future studies are needed to confirm the few existing results, and then to elucidate whether DNA methylation changes are the cause or consequence of AUDs. SCIENTIFIC SIGNIFICANCE DNA methylation profiles may be used to assess AUD status or monitor AUD treatment response. (Am J Addict 2017;26:502-515).
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Affiliation(s)
- Huiping Zhang
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.,VA Connecticut Healthcare System, West Haven, Connecticut
| | - Joel Gelernter
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.,VA Connecticut Healthcare System, West Haven, Connecticut.,Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.,Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut
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Srinivasan P, Thrower EC, Gorelick FS, Said HM. Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Am J Physiol Gastrointest Liver Physiol 2016; 310:G874-83. [PMID: 26999808 PMCID: PMC4888549 DOI: 10.1152/ajpgi.00461.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/11/2016] [Indexed: 01/31/2023]
Abstract
Thiamin is essential for normal metabolism in pancreatic acinar cells (PAC) and is obtained from their microenvironment through specific plasma-membrane transporters, converted to thiamin pyrophosphate (TPP) in the cytoplasm, followed by uptake of TPP by mitochondria through the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). TPP is essential for normal mitochondrial function. We examined the effect of long-term/chronic exposure of PAC in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type or transgenic mice carrying the SLC25A19 promoter) of the cigarette smoke toxin, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on the MTPP uptake process. Our in vitro and in vivo findings demonstrate that NNK negatively affects MTPP uptake and reduced expression of MTPPT protein, MTPPT mRNA, and heterogenous nuclear RNA, as well as SLC25A19 promoter activity. The effect of NNK on Slc25a19 transcription was neither mediated by changes in expression of transcriptional factor NFY-1 (known to drive SLC25A19 transcription), nor due to changes in methylation profile of the Slc25a19 promoter. Rather, it appears to be due to changes in histone modifications that involve significant decreases in histone H3K4-trimethylation and H3K9-acetylation (activation markers). The effect of NNK on MTPPT function is mediated through the nonneuronal α7-nicotinic acetylcholine receptor (α7-nAChR), as indicated by both in vitro (using the nAChR antagonist mecamylamine) and in vivo (using an α7-nAchR(-/-) mouse model) studies. These findings demonstrate that chronic exposure of PAC to NNK negatively impacts PAC MTPP uptake. This effect appears to be exerted at the level of Slc25a19 transcription, involve epigenetic mechanism(s), and is mediated through the α7-nAchR.
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Affiliation(s)
- Padmanabhan Srinivasan
- 1Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; ,2Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California;
| | - Edwin C. Thrower
- 3Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut;
| | - Fred S. Gorelick
- 4Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut; and ,5Veterans Affairs Healthcare System, West Haven, Connecticut
| | - Hamid M. Said
- 1Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; ,2Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California;
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Subramanian VS, Srinivasan P, Said HM. Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Am J Physiol Cell Physiol 2016; 311:C129-35. [PMID: 27122159 DOI: 10.1152/ajpcell.00042.2016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/20/2016] [Indexed: 12/21/2022]
Abstract
Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells including pancreatic acinar cells (PACs). PACs obtain AA from their surroundings via transport across the cell membrane. Chronic alcohol exposure negatively affects body AA homeostasis; it also inhibits uptake of other micronutrients into PACs, but its effect on AA uptake is not clear. We examined this issue using both in vitro (266-6 cells) and in vivo (mice) models of chronic alcohol exposure. First, we determined the relative expression of the AA transporters 1 and 2 [i.e., sodium-dependent vitamin C transporter-1 (SVCT-1) and SVCT-2] in mouse and human PACs and found SVCT-2 to be the predominant transporter. Chronic exposure of 266-6 cells to alcohol significantly inhibited AA uptake and caused a marked reduction in SVCT-2 expression at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Similarly, chronic alcohol feeding of mice significantly inhibited AA uptake and caused a marked reduction in level of expression of the SVCT-2 protein, mRNA, and hnRNA. These findings suggest possible involvement of transcriptional mechanism(s) in mediating chronic alcohol effect on AA uptake by PACs. We also observed significant epigenetic changes (histone modifications) in the Slc23a2 gene (reduction in H3K4me3 level and an increase in H3K27me3 level) in the alcohol-exposed 266-6 cells. These findings show that chronic alcohol exposure inhibits PAC AA uptake and that the effect is mediated, in part, at the level of transcription of the Slc23a2 gene and may involve epigenetic mechanism(s).
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Affiliation(s)
- Veedamali S Subramanian
- Department of Medicine, University of California, Irvine, California; Department of Physiology, University of California, Irvine, California; Department of Biophysics, University of California, Irvine, California; Department of Veterans Affairs Medical Center, Long Beach, California
| | - Padmanabhan Srinivasan
- Department of Medicine, University of California, Irvine, California; Department of Physiology, University of California, Irvine, California; Department of Biophysics, University of California, Irvine, California; Department of Veterans Affairs Medical Center, Long Beach, California
| | - Hamid M Said
- Department of Medicine, University of California, Irvine, California; Department of Physiology, University of California, Irvine, California; Department of Biophysics, University of California, Irvine, California; Department of Veterans Affairs Medical Center, Long Beach, California
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Timms JA, Relton CL, Rankin J, Strathdee G, McKay JA. DNA methylation as a potential mediator of environmental risks in the development of childhood acute lymphoblastic leukemia. Epigenomics 2016; 8:519-36. [PMID: 27035209 PMCID: PMC4928498 DOI: 10.2217/epi-2015-0011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 01/22/2016] [Indexed: 11/21/2022] Open
Abstract
5-year survival rate for childhood acute lymphoblastic leukemia (ALL) has risen to approximately 90%, yet the causal disease pathway is still poorly understood. Evidence suggests multiple 'hits' are required for disease progression; an initial genetic abnormality followed by additional secondary 'hits'. It is plausible that environmental influences may trigger these secondary hits, and with the peak incidence of diagnosis between 2 and 5 years of age, early life exposures are likely to be key. DNA methylation can be modified by many environmental exposures and is dramatically altered in cancers, including childhood ALL. Here we explore the potential that DNA methylation may be involved in the causal pathway toward disease by acting as a mediator between established environmental factors and childhood ALL development.
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Affiliation(s)
- Jessica A Timms
- Institute of Health & Society, Newcastle University, Newcastle, UK
| | - Caroline L Relton
- MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, UK
| | - Judith Rankin
- Institute of Health & Society, Newcastle University, Newcastle, UK
| | - Gordon Strathdee
- Northern Institute for Cancer Research, Newcastle University, UK
| | - Jill A McKay
- Institute of Health & Society, Newcastle University, Newcastle, UK
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DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. Sci Rep 2016; 6:19430. [PMID: 26763658 PMCID: PMC4725922 DOI: 10.1038/srep19430] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 12/14/2015] [Indexed: 02/03/2023] Open
Abstract
DNA methylome alterations in the prefrontal cortex (PFC) may contribute to risk for alcohol use disorders (AUDs). We examined postmortem PFC DNA methylomes of 16 male and seven female pairs of AUD and control subjects using Illumina's HumanMethylation450 BeadChip assays. In male AUD subjects, 1,812 CpGs (1,099 genes) were differentially methylated (9.5 × 10(-9) ≤ Pnominal ≤ 7.2 × 10(-4), q < 0.05). In females, no CpGs were associated with AUDs after multiple testing correction (q > 0.05). Twenty-one AUD-associated co-methylation modules were identified in males by co-methylation analysis. The 1,812 CpGs were over-presented by two AUD-associated co-methylation modules (Mturquoise: 1,048 CpGs/683 genes; Mblue: 429 CpGs/304 genes) (Phyper ≤ 0.001). Biological processes enriched for genes in these two modules included neural development and transcriptional regulation. Genes mapped by CpGs in these two modules were enriched in genome-wide association study-identified genes with variants associated with four substance dependence phenotypes or five psychiatric disorders. Additionally, 106 of the 1,812 CpGs were mapped to 93 genes (e.g., AUD-associated genes GRIK3, GRIN2C, and GABRA1) with differential expression in postmortem PFC of male AUD subjects. Our study demonstrates that DNA methylation alterations in the PFC are associated with (and might result in) increased risk of AUDs, and there was a complex DNA methylation-gene expression relationship.
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Srinivasan P, Nabokina S, Said HM. Chronic alcohol exposure affects pancreatic acinar mitochondrial thiamin pyrophosphate uptake: studies with mouse 266-6 cell line and primary cells. Am J Physiol Gastrointest Liver Physiol 2015; 309:G750-8. [PMID: 26316591 PMCID: PMC4628969 DOI: 10.1152/ajpgi.00226.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 08/21/2015] [Indexed: 01/31/2023]
Abstract
Thiamin is essential for normal metabolic activity of all mammalian cells, including those of the pancreas. Cells obtain thiamin from their surroundings and enzymatically convert it into thiamin pyrophosphate (TPP) in the cytoplasm; TPP is then taken up by mitochondria via a specific carrier the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene). Chronic alcohol exposure negatively impacts the health of pancreatic acinar cells (PAC), but its effect on physiological/molecular parameters of MTPPT is not known. We addressed this issue using mouse pancreatic acinar tumor cell line 266-6 and primary PAC of wild-type and transgenic mice carrying the SLC25A19 promoter that were fed alcohol chronically. Chronic alcohol exposure of 266-6 cells (but not to its nonoxidative metabolites ethyl palmitate and ethyl oleate) led to a significant inhibition in mitochondrial TPP uptake, which was associated with a decreased expression of MTPPT protein, mRNA, and activity of the SLC25A19 promoter. Similarly, chronic alcohol feeding of mice led to a significant inhibition in expression of MTPPT protein, mRNA, heterogeneous nuclear RNA, as well as in activity of SLC25A19 promoter in PAC. While chronic alcohol exposure did not affect DNA methylation of the Slc25a19 promoter, a significant decrease in histone H3 euchromatin markers and an increase in H3 heterochromatin marker were observed. These findings show, for the first time, that chronic alcohol exposure negatively impacts pancreatic MTPPT, and that this effect is exerted, at least in part, at the level of Slc25a19 transcription and appears to involve epigenetic mechanism(s).
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Affiliation(s)
- Padmanabhan Srinivasan
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Svetlana Nabokina
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Hamid M. Said
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
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Current and Future Prospects for Epigenetic Biomarkers of Substance Use Disorders. Genes (Basel) 2015; 6:991-1022. [PMID: 26473933 PMCID: PMC4690026 DOI: 10.3390/genes6040991] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 09/16/2015] [Accepted: 09/22/2015] [Indexed: 01/30/2023] Open
Abstract
Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol) related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence.
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Gurbanov R, Simsek Ozek N, Gozen AG, Severcan F. Quick Discrimination of Heavy Metal Resistant Bacterial Populations Using Infrared Spectroscopy Coupled with Chemometrics. Anal Chem 2015; 87:9653-61. [DOI: 10.1021/acs.analchem.5b01659] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Rafig Gurbanov
- Department of Biochemistry and ‡Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey
| | - Nihal Simsek Ozek
- Department of Biochemistry and ‡Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey
| | - Ayse Gul Gozen
- Department of Biochemistry and ‡Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey
| | - Feride Severcan
- Department of Biochemistry and ‡Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey
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Januar V, Saffery R, Ryan J. Epigenetics and depressive disorders: a review of current progress and future directions. Int J Epidemiol 2015; 44:1364-87. [DOI: 10.1093/ije/dyu273] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2014] [Indexed: 12/26/2022] Open
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Lee BY, Park SY, Ryu HM, Shin CY, Ko KN, Han JY, Koren G, Cho YH. Changes in the methylation status of DAT, SERT, and MeCP2 gene promoters in the blood cell in families exposed to alcohol during the periconceptional period. Alcohol Clin Exp Res 2015; 39:239-50. [PMID: 25656446 DOI: 10.1111/acer.12635] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/12/2014] [Indexed: 11/27/2022]
Abstract
BACKGROUND Alcohol exposure has been shown to cause devastating effects on neurobehavioral development in numerous animal and human studies. The alteration of DNA methylation levels in gene-specific promoter regions has been investigated in some studies of human alcoholics. This study was aimed to investigate whether social alcohol consumption during periconceptional period is associated with epigenetic alteration and its generational transmission in the blood cells. METHODS We investigated patterns of alcohol intake in a prospective cohort of 355 pairs of pregnant women and their spouses who reported alcohol intake during the periconceptional period. A subpopulation of 164 families was established for the epigenetic study based on the availability of peripheral blood and cord blood DNA. The relative methylation changes of dopamine transporter (DAT), serotonin transporter (SERT), and methyl CpG binding protein 2 (MeCP2) gene promoters were analyzed using methylation-specific endonuclease digestion followed by quantitative real-time polymerase chain reaction. RESULTS The relative methylation level of the DAT gene promoter was decreased in the group of mothers reporting above moderate drinking (p = 0.029) and binge drinking (p = 0.037) during pregnancy. The relative methylation level of the DAT promoter was decreased in the group of fathers reporting heavy binge drinking (p = 0.003). The relative methylation levels of the SERT gene promoter were decreased in the group of newborns of light drinking mothers before pregnancy (p = 0.012) and during pregnancy (p = 0.003). The methylation level in the MeCP2 promoter region of babies whose mothers reported above moderate drinking during pregnancy was increased (p = 0.02). In addition, methylation pattern in the DAT promoter region of babies whose fathers reported heavy binge drinking was decreased (p = 0.049). CONCLUSIONS These findings suggest that periconceptional alcohol intake may cause epigenetic changes in specific locus of parental and newborn genomes as follows: Alcohol consumption decreases the methylation level of the DAT promoter region of the parent themselves, maternal alcohol drinking during the periconceptional period decreases the methylation level of the SERT promoter region of newborns, and maternal alcohol consumption increases the methylation level of the MeCP2 promoter region of newborns.
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Affiliation(s)
- Bom-Yi Lee
- Laboratory of Medical Genetics, Cheil General Hospital and Women's Healthcare Center, Seoul, Korea; Department of Medical Genetics, College of Medicine, Hanyang University, Seoul, Korea
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Qiang M, Li JG, Denny AD, Yao JM, Lieu M, Zhang K, Carreon S. Epigenetic mechanisms are involved in the regulation of ethanol consumption in mice. Int J Neuropsychopharmacol 2015; 18:pyu072. [PMID: 25522411 PMCID: PMC4368896 DOI: 10.1093/ijnp/pyu072] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Repeated alcohol exposure is known to increase subsequent ethanol consumption in mice. However, the underlying mechanisms have not been fully elucidated. One postulated mechanism involves epigenetic modifications, including histone modifications and DNA methylation of relevant genes such as NR2B or BDNF. METHODS To investigate the role of epigenetic mechanisms in the development of alcohol drinking behavior, an established chronic intermittent ethanol exposure reinforced ethanol drinking mouse model with vapor inhalation over two 9-day treatment regimens was used. The DNA methyltransferase inhibitor, 5-azacytidine or the histone deacetylase inhibitor, Trichostatin A was administered (intraperitoneally) to C57BL/6 mice 30 min before daily exposure to chronic intermittent ethanol. Changes in ethanol consumption were measured using the 2-bottle choice test. RESULTS The results indicated that systemic administration of Trichostatin A (2.5 µg/g) facilitated chronic intermittent ethanol-induced ethanol drinking, but systemic administration of 5-azacytidine (2 µg/g) did not cause the same effect. However, when 5-azacytidine was administered by intracerebroventricular injection, it facilitated chronic intermittent ethanol-induced ethanol drinking. Furthermore, the increased drinking caused by chronic intermittent ethanol was prevented by injection of a methyl donor, S-adenosyl-L-methionine. To provide evidence that chronic intermittent ethanol- or Trichostatin A-induced DNA demethylation and histone modifications of the NR2B promoter may underlie the altered ethanol consumption, we examined epigenetic modifications and NR2B expression in the prefrontal cortex of these mice. Chronic intermittent ethanol or Trichostatin A decreased DNA methylation and increased histone acetylation in the NR2B gene promoter, as well as mRNA levels of NR2B in these mice. CONCLUSIONS Taken together, these results indicate that epigenetic modifications are involved in regulating ethanol drinking behavior, partially through altering NR2B expression.
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Affiliation(s)
- Mei Qiang
- Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (Drs Qiang, Li, Denny, Lieu, and Carreon); Department of Neurology, Third Hospital of Guangxi Medical University, Nanning, Guangxi, China (Dr Yao); Department of Psychiatry, First Clinical Medical College (Dr Zhang), and School of Public Health, Shanxi Medical University, Taiyuan, China (Dr Qiang).
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Liyanage VRB, Zachariah RM, Davie JR, Rastegar M. Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements. Exp Neurol 2015; 265:102-17. [PMID: 25620416 DOI: 10.1016/j.expneurol.2015.01.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 12/23/2014] [Accepted: 01/18/2015] [Indexed: 11/29/2022]
Abstract
Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in the brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposure-induced neurological symptoms. However, the underlying molecular mechanisms of ethanol-induced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC). Previously, we demonstrated the impact of DNA methylation at the Mecp2 regulatory elements (REs) on Mecp2/MeCP2 expression in vitro and in vivo. Here, we studied whether altered DNA methylation at these REs is associated with the Mecp2/MeCP2 misexpression induced by ethanol. Binge-like and continuous ethanol exposure upregulated Mecp2/MeCP2, while ethanol withdrawal downregulated its expression. DNA methylation analysis by methylated DNA immunoprecipitation indicated that increased 5-hydroxymethylcytosine (5hmC) and decreased 5-methylcytosine (5mC) enrichment at specific REs were associated with upregulated Mecp2/MeCP2 following continuous ethanol exposure. The reduced Mecp2/MeCP2 expression upon ethanol withdrawal was associated with reduced 5hmC and increased 5mC enrichment at these REs. Moreover, ethanol altered global DNA methylation (5mC and 5hmC). Under the tested conditions, ethanol had minimal effects on NSC cell fate commitment, but caused changes in neuronal morphology and glial cell size. Taken together, our data represent an epigenetic mechanism for ethanol-mediated misexpression of Mecp2/MeCP2 in differentiating embryonic brain cells. We also show the potential role of DNA methylation and MeCP2 in alcohol-related neurological disorders, specifically Fetal Alcohol Spectrum Disorders.
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Affiliation(s)
- Vichithra Rasangi Batuwita Liyanage
- Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada; Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada.
| | - Robby Mathew Zachariah
- Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada; Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada.
| | - James Ronald Davie
- Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada.
| | - Mojgan Rastegar
- Regenerative Medicine Program, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada; Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba R3E 0J9, Canada.
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Hillemacher T, Weinland C, Lenz B, Kraus T, Heberlein A, Glahn A, Muschler MAN, Bleich S, Kornhuber J, Frieling H. DNA methylation of the LEP gene is associated with craving during alcohol withdrawal. Psychoneuroendocrinology 2015; 51:371-7. [PMID: 25462909 DOI: 10.1016/j.psyneuen.2014.10.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/08/2014] [Accepted: 10/13/2014] [Indexed: 01/10/2023]
Abstract
Different studies have described evidence for an association between leptin serum levels and craving in alcohol dependent patients. As leptin expression is regulated by DNA methylation we investigated changes of DNA methylation of the LEP gene promoter region in alcohol dependent patients undergoing withdrawal. Results show that low methylation status is associated with increasing serum leptin levels and elevation of craving for alcohol in the referring patients group. These findings point towards a pathophysiological relevance of changes in DNA methylation of the LEP gene promoter region in alcohol dependence.
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Affiliation(s)
- Thomas Hillemacher
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany; Molecular Neurosciences Laboratory, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
| | - Christian Weinland
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
| | - Thomas Kraus
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany; Frankenalb-Klinik Engelthal, Nürnberg, Germany
| | - Annemarie Heberlein
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Alexander Glahn
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Marc A N Muschler
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany; Molecular Neurosciences Laboratory, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Stefan Bleich
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany; Molecular Neurosciences Laboratory, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany
| | - Helge Frieling
- Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany; Molecular Neurosciences Laboratory, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
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Kim G, Lee HS, Seok Bang J, Kim B, Ko D, Yang M. A current review for biological monitoring of manganese with exposure, susceptibility, and response biomarkers. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2015; 33:229-54. [PMID: 26023759 DOI: 10.1080/10590501.2015.1030530] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers.
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Affiliation(s)
- Gyuri Kim
- a Research Center for Cell Fate Control, Department of Toxicology, College of Pharmacy, Sookmyung Women's University , Seoul , Republic of Korea
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Bleich S, Semmler A, Frieling H, Thumfart L, Muschler M, Hillemacher T, Kornhuber J, Kallweit U, Simon M, Linnebank M. Genetic variants of methionine metabolism and DNA methylation. Epigenomics 2014; 6:585-91. [DOI: 10.2217/epi.14.54] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aim: Altered DNA methylation is associated with important and common pathologies such as cancer. The origin of altered DNA methylation is unknown. The methyl groups for DNA methylation are provided by methionine metabolism. This metabolism is characterized by a high interindividual variability, which is in part explained by genetic variants. Methods: In a cohort of 313 individuals derived from a family-based study with index cases of cerebrovascular disease, we analyzed whether global methylation of leukocyte DNA was associated with age, gender, homocysteine plasma levels or functionally relevant genetic variants. Results: We observed an association of the G-allele of the methionine synthase variant c.2756A>G (D919G) with global methylation (% methylation ± 1 SD, AA: 41.3 ± 14.9; AG: 36.4 ± 18.2; GG: 30.8 ± 16.9; F = 4.799; p = 0.009). The methionine synthase variant c.2756A>G is associated with various types of cancer. Conclusion: Our data suggest that an impact on DNA methylation may contribute to the clinical relevance of the methionine synthase variant.
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Affiliation(s)
- Stefan Bleich
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Alexander Semmler
- Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
| | - Helge Frieling
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - L Thumfart
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Marc Muschler
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Thomas Hillemacher
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Johannes Kornhuber
- Molecular Neuroscience Laboratory, Department of Psychiatry, Social Psychiatry & Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Ulf Kallweit
- Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
| | - Matthias Simon
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
| | - Michael Linnebank
- Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland
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Srinivasan P, Kapadia R, Biswas A, Said HM. Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms. Am J Physiol Gastrointest Liver Physiol 2014; 307:G941-9. [PMID: 25214397 PMCID: PMC4250263 DOI: 10.1152/ajpgi.00278.2014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 09/04/2014] [Indexed: 01/31/2023]
Abstract
Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5'-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na(+) dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.
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Affiliation(s)
- Padmanabhan Srinivasan
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Rubina Kapadia
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Arundhati Biswas
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Hamid M Said
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; and Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
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Brucato N, DeLisi LE, Fisher SE, Francks C. Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2014; 165B:555-63. [PMID: 25111784 DOI: 10.1002/ajmg.b.32258] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 06/26/2014] [Indexed: 12/25/2022]
Abstract
Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context.
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Affiliation(s)
- Nicolas Brucato
- Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
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44
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Zhu B, Wu X, Zhi X, Liu L, Zheng Q, Sun G. Methylenetetrahydrofolate reductase C677T polymorphism and type 2 diabetes mellitus in Chinese population: a meta-analysis of 29 case-control studies. PLoS One 2014; 9:e102443. [PMID: 25047451 PMCID: PMC4105552 DOI: 10.1371/journal.pone.0102443] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 06/19/2014] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. METHODS We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined. RESULTS 29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42-2.02), recessive (OR: 1.48, 95% CI: 1.21-1.80), homozygous (OR: 1.89, 95% CI: 1.47-2.42), heterozygous (OR: 1.58, 95% CI: 1.33-1.87), and additive (OR: 1.46, 95% CI: 1.28-1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable. CONCLUSIONS There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population.
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Affiliation(s)
- Bo Zhu
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
- Liaoning Academy of Safety Science, Shenyang, People's Republic of China
| | - Xiaomei Wu
- Department of Clinical Epidemiology and Evidence Medicine, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Xueyuan Zhi
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
| | - Lei Liu
- Key Laboratory of Endocrine diseases in Liaoning Province, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Quanmei Zheng
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
| | - Guifan Sun
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China
- * E-mail:
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Liu J, Chen J, Ehrlich S, Walton E, White T, Perrone-Bizzozero N, Bustillo J, Turner JA, Calhoun VD. Methylation patterns in whole blood correlate with symptoms in schizophrenia patients. Schizophr Bull 2014; 40:769-76. [PMID: 23734059 PMCID: PMC4059425 DOI: 10.1093/schbul/sbt080] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
DNA methylation, one of the main epigenetic mechanisms to regulate gene expression, appears to be involved in the development of schizophrenia (SZ). In this study, we investigated 7562 DNA methylation markers in blood from 98 SZ patients and 108 healthy controls. A linear regression model including age, gender, race, alcohol, nicotine and cannabis use status, and diagnosis was implemented to identify C-phosphate-G (CpG) sites significantly associated with diagnosis. These CpG sites were further validated using an independent data set. Sixteen CpG sites were identified with hyper- or hypomethylation in patients. A further verification of expression of the corresponding genes identified 7 genes whose expression levels were also significantly altered in patients. While such altered methylation patterns showed no correlation with disorganized symptoms and negative symptoms in patients, 11 CpG sites significantly correlated with reality distortion symptoms. The direction of the correlations indicates that methylation changes possibly play a protective mechanism to lessen delusion and hallucination symptoms in patients. Pathway analyses showed that the most significant biological function of the differentially methylated CpGs is inflammatory response with CD224, LAX1, TXK, PRF1, CD7, MPG, and MPO genes directly involved in activations of T cells, B cells, and natural killer cells or in cytotoxic reaction. Our results suggest that such methylation changes may modulate aspects of the immune response and hence protect against the neurobiological substrate of reality distortion symptoms in SZ patients.
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Affiliation(s)
- Jingyu Liu
- The Mind Research Network, Albuquerque, NM; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM;
| | - Jiayu Chen
- The Mind Research Network, Albuquerque, NM;,Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM
| | - Stefan Ehrlich
- Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;,MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA
| | - Esther Walton
- Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;,MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA
| | - Tonya White
- Department of Child and Adolescent Psychiatry, Erasmus University, Rotterdam, Netherlands
| | | | - Juan Bustillo
- Department of Psychiatry, University of New Mexico, Albuquerque, NM
| | - Jessica A. Turner
- The Mind Research Network, Albuquerque, NM;,Department of Psychiatry, University of New Mexico, Albuquerque, NM
| | - Vince D. Calhoun
- The Mind Research Network, Albuquerque, NM;,Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM;,Department of Neurosciences, University of New Mexico, Albuquerque, NM;,Department of Psychiatry, University of New Mexico, Albuquerque, NM
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Kruman II, Fowler AK. Impaired one carbon metabolism and DNA methylation in alcohol toxicity. J Neurochem 2014; 129:770-80. [PMID: 24521073 DOI: 10.1111/jnc.12677] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 01/30/2014] [Accepted: 02/03/2014] [Indexed: 12/30/2022]
Abstract
Excessive alcohol consumption is a prominent problem and one of the major causes of mortality and morbidity around the world. Long-term, heavy alcohol consumption is associated with a number of deleterious health consequences, such as cancer, heart and liver disease, a variety of neurological, cognitive, and behavioral deficits. Alcohol consumption is also associated with developmental defects. The causes of alcohol-induced toxicity are presently unclear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with folic acid/homocysteine or one-carbon metabolism (OCM). OCM is a major donor of methyl groups for methylation, particularly DNA methylation critical for epigenetic regulation of gene expression, and its disturbance may compromise DNA methylation, thereby affecting gene expression. OCM disturbance mediated by nutrient deficits is a well-known risk factor for various disorders and developmental defects (e.g., neural tube defects). In this review, we summarize the role of OCM disturbance and associated epigenetic aberrations in chronic alcohol-induced toxicity. In this review, we summarize the role of one-carbon metabolism (OCM) aberrations in chronic alcohol-induced toxicity. OCM is a major donor of methyl groups for methylation reactions, particularly DNA methylation critical for epigenetic regulation of gene expression. Alcohol interference with OCM and consequent reduced availability of methyl groups, improper DNA methylation, and aberrant gene expression can play a causative role in alcohol toxicity.
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Affiliation(s)
- Inna I Kruman
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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47
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Nieratschker V, Grosshans M, Frank J, Strohmaier J, von der Goltz C, El-Maarri O, Witt SH, Cichon S, Nöthen MM, Kiefer F, Rietschel M. Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age. Addict Biol 2014; 19:305-11. [PMID: 22506971 DOI: 10.1111/j.1369-1600.2012.00459.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol-dependent patients and population-based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing-specific process, our findings suggest that hypermethylation in alcohol-dependent patients is a consequence, rather than a cause, of the disorder.
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Affiliation(s)
- Vanessa Nieratschker
- Departments of Genetic Epidemiology in Psychiatry Addictive Behavior and Addiction Medicine Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Germany, Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Germany Institute of Neuroscience and Medicine, Research Centre Jülich, Germany Department of Genomics, Life & Brain Center Institute of Human Genetics University of Bonn, Germany and German Center for Neurodegenerative Disorders (DZNE), Germany
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48
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Glahn A, Riera Knorrenschild R, Rhein M, Haschemi Nassab M, Gröschl M, Heberlein A, Muschler M, Frieling H, Bleich S, Hillemacher T. Alcohol-induced changes in methylation status of individual CpG sites, and serum levels of vasopressin and atrial natriuretic peptide in alcohol-dependent patients during detoxification treatment. Eur Addict Res 2014; 20:143-50. [PMID: 24356727 DOI: 10.1159/000357473] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 11/19/2013] [Indexed: 11/19/2022]
Abstract
Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.
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Affiliation(s)
- Alexander Glahn
- Center for Addiction Research (CARe), Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
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New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int J Hepatol 2014; 2014:513787. [PMID: 24868470 PMCID: PMC4020372 DOI: 10.1155/2014/513787] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 04/07/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also in vivo in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.
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50
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Krishnan HR, Sakharkar AJ, Teppen TL, Berkel TDM, Pandey SC. The epigenetic landscape of alcoholism. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 115:75-116. [PMID: 25131543 DOI: 10.1016/b978-0-12-801311-3.00003-2] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, hold great therapeutic potential in the treatment and prevention of alcoholism.
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Affiliation(s)
- Harish R Krishnan
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
| | - Amul J Sakharkar
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
| | - Tara L Teppen
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
| | - Tiffani D M Berkel
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
| | - Subhash C Pandey
- Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA.
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