Setdb1 Histone Methyltransferase Regulates Mood-Related Behaviors and Expression of the NMDA Receptor Subunit NR2B
Open accessAbstract
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.
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Setdb1 regulation led to anhedonia, despair, and learned helplessness in behavioral paradigms.
“This regulation led to anhedonia, despair, and learned helplessness in behavioral paradigms.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [172]
The Results section reports the opposite direction: increased Setdb1 expression was associated with increased sucrose consumption, decreased despair-related immobility, and faster recovery from learned helplessness. The Discussion describes these findings as an antidepressant-like phenotype in paradigms related to anhedonia, despair, and helplessness—not as Setdb1 regulation leading to those states. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredHigher expression of Setdb1, an H3K9-specific HMT in the mouse forebrain, was associated with changes in NMDA receptor subunit composition and other molecular modifications resulting from suppressive chromatin remodeling at specific target genes.
“Higher expression of Setdb1, an H3K9-specific HMT in the mouse forebrain, was associated with changes in the composition of NMDA receptor subunits, as well as other molecular modifications resulting from suppressive chromatin remodeling at specific target genes.172”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [172]
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References 93 · Cited by 118
- Authors
- Jiang, Y., Jakovcevski, M., Bharadwaj, R., Connor, C., Schroeder, F. A., Lin, C. L., Straubhaar, J., Martin, G., & Akbarian, S.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Akbarian, Schahram
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-05-26
- Volume
- 30
- Issue
- 21
- Pages
- 7152-7167
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2893142
- OpenAlex
- W2071781936
- Cited by
- 118
- References
- 93
- Citations by year
- 2026: 4 · 2024: 3 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 11 · 2019: 9 · 2018: 1 · 2017: 7 · 2016: 9 · 2015: 3 · 2014: 10 · 2013: 16 · 2012: 14
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (RC1MH088047, R01MH086509)
- National Institute on Drug Abuse (R01DA017660)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- SETDB1, histone methyltransferase, H3K9 methylation, NMDA receptor subunit composition, anhedonia, learned helplessness, antidepressant-like behavior, chromatin looping, hippocampus, ventral striatum, NMDA receptor desensitization, Ro 25-6981, ionotropic glutamate receptors, emotional behavior
- MeSH terms
- Adaptation, Ocular, Affect, Age Factors, Animals, Animals, Newborn, Avoidance Learning, Behavior, Animal, Cells, Cultured, Chromatin, Conditioning, Psychological, Electroshock, Exploratory Behavior, Fear, Food Preferences, Gene Expression Regulation, Hippocampus, Humans, Membrane Potentials, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Histone-Lysine N-Methyltransferase, Protein Methyltransferases, Sucrose, Sweetening Agents, Transfection, Receptors, N-Methyl-D-Aspartate, Patch-Clamp Techniques, Excitatory Amino Acid Agents, Maze Learning, Excitatory Postsynaptic Potentials, RNA, Small Interfering, Immobility Response, Tonic, Chromatin Immunoprecipitation, Green Fluorescent Proteins, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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