Effect of mood stabilizers on DNA methylation in human neuroblastoma cells
Open accessAbstract
Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lithium, carbamazepine and quetiapine, often prescribed for bipolar disorder, are associated with decreased methylation of SLC6A4.
“For example, Lithium, Carbamazepine and Quetiapine, often prescribed for the treatment of BD, are associated with decrease methylation of SLC6A4 (Asai et al., 2013; Sugawara et al., 2015), in contrast with the hypermethylation reported in BD in that gene (Table 2).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Asai et al., 2013
Cites
DNA Methylation-Related Chromatin Remodeling in Activity-Dependent <i>Bdnf</i> Gene Regulation
Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., & Sun, Y. E. (2003) · Science · doi:10.1126/science.1090842 · Cited by 1,405 · see citing works
Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects
Keller, S., Sarchiapone, M., Zarrilli, F., Videtič, A., Ferraro, A., Carli, V., Sacchetti, S., Lembo, F., Angiolillo, A., Jovanovic, N., et al. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.9 · Cited by 379 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Numata, S., Ishii, K., Tajima, A., Iga, J.-I., Kinoshita, M., Watanabe, S., Umehara, H., Fuchikami, M., Okada, S., Boku, S., et al. (2015) · Epigenetics · doi:10.1080/15592294.2014.1003743 · Cited by 79 · see citing works
Kaut, O., Schmitt, I., Hofmann, A., Hoffmann, P., Schlaepfer, T. E., Wüllner, U., & Hurlemann, R. (2015) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-014-0572-y · Cited by 68 · see citing works
Kim, K. C., Choi, C. S., Kim, J.-W., Han, S.-H., Cheong, J. H., Ryu, J. H., & Shin, C. Y. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-8987-z · Cited by 60 · see citing works
Can epigenetics shine a light on the biological pathways underlying major mental disorders?
Alameda, L., Trotta, G., Quigley, H., Rodriguez, V., Gadelrab, R., Dwir, D., Dempster, E., Wong, C. C. Y., & Forti, M. D. (2022) · Psychological Medicine · doi:10.1017/s0033291721005559 · Cited by 60 · see citing works
“(2013) Candidate gene Blood Depression CA → ↑SLC6A4 → clinical severity”
BackgroundInfluentialEpigenetics in bipolar disorder: a critical review of the literature
Legrand, A., Iftimovici, A., Khayachi, A., & Chaumette, B. (2021) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000267 · Cited by 48 · see citing works
Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia
Lee, S.-A., & Huang, K.-C. (2016) · BMC Medical Genomics · doi:10.1186/s12920-016-0229-y · Cited by 46 · see citing works
Effects of quetiapine on DNA methylation in neuroblastoma cells
Sugawara, H., Bundo, M., Asai, T., Sunaga, F., Ueda, J., Ishigooka, J., Kasai, K., Kato, T., & Iwamoto, K. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.08.010 · Cited by 32 · see citing works
Self-citation
- Authors
- Asai, T., Bundo, M., Sugawara, H., Sunaga, F., Ueda, J., Tanaka, G., Ishigooka, J., Kasai, K., Kato, T., & Iwamoto, K.
- Affiliations
- The University of Tokyo (JP)
- Tokyo Women's Medical University (JP)
- RIKEN (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Iwamoto, Kazuya
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-11-01
- Volume
- 16
- Issue
- 10
- Pages
- 2285-2294
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2141017448
- Cited by
- 68
- References
- 2
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 4 · 2016: 9 · 2015: 6 · 2014: 6 · 2013: 1
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Dainippon Sumitomo Pharma
- Kyowa Hakko Kirin
- Meiji Seika Pharma
- Astellas Foundation for Research on Metabolic Disorders
- MSD K.K.
- Eli Lilly Japan
- Sanofi K.K.
- Japan Society for the Promotion of Science
- Janssen Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- mood stabilizers, DNA methylation, epigenetics, lithium, valproic acid, carbamazepine, neuroblastoma cells, serotonin transporter, brain-derived neurotrophic factor, promoter methylation, bipolar disorder, suicide, mental illness
- MeSH terms
- Carbamazepine, Humans, Neuroblastoma, Promoter Regions, Genetic, Valproic Acid, Gene Expression Regulation, Neoplastic, Lithium Compounds, Antimanic Agents, CpG Islands, DNA Methylation, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Cell Line, Tumor, Serotonin Plasma Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
