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Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
Open accessAbstract
Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.
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“Enduring transcriptional alterations were observed in the ventral tegmental area (VTA) in ELS, mediated by the developmental transcription factor orthodenticle homeobox 2 (OTX2).”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [211]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“ELS-induced depression susceptibility was caused by decreased histone methylation (H3K79me2) and induction of the DOT1L and KDM2B enzymes that regulate this histone methylation in D2-type medium spiny neurons.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [211]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Another recent publication offers evidence of the potential for stressful experiences early in life to affect future behavior by influencing the rates of gene transcription and translation in brain cells [24].”
From Genes, Heritability, ‘Race’, and Intelligence: Misapprehensions and Implications (2022) · cites this paper as [24]
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“systemic delivery of DOT1L inhibitor reversed ELS-induced behavioral deficits without detectable side effects, suggesting a potential therapeutic target.211”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [211]
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“The same stress model211 revealed long-lasting histone modifications in the NAc after ELS.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [211]
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“Furthermore, histone methylation (H3K4me1) changes were found in genes targeted by OTX2 binding.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [211]
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Cites
D 1 and D 2 Dopamine Receptor-regulated Gene Expression of Striatonigral and Striatopallidal Neurons
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Self-citationA standardized protocol for repeated social defeat stress in mice
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g:Profiler—a web server for functional interpretation of gene lists (2016 update)
Reimand, J., Arak, T., Adler, P., Kolberg, L., Reisberg, S., Peterson, H., & Vilo, J. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw199 · Cited by 1,229
Sex-specific transcriptional signatures in human depression
Labonté, B., Engmann, O., Purushothaman, I., Menard, C., Wang, J., Tan, C., Scarpa, J. R., Moy, G., Loh, Y.-H. E., Cahill, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4386 · Cited by 748
Self-citationEndocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models
Kreitzer, A. C., & Malenka, R. C. (2007) · Nature · doi:10.1038/nature05506 · Cited by 735
Apigenin in cancer therapy: anti-cancer effects and mechanisms of action
Yan, X., Qi, M., Li, P., Zhan, Y., & Shao, H. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0179-x · Cited by 569
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Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression
Bagot, R. C., Parise, E. M., Peña, C. J., Zhang, H.-X., Maze, I., Chaudhury, D., Persaud, B., Cachope, R., Bolaños-Guzmán, C. A., Cheer, J. F., et al. (2015) · Nature Communications · doi:10.1038/ncomms8062 · Cited by 491
Self-citationNLRP3 inflammasome in neurological diseases, from functions to therapies
Song, L., Pei, L., Yao, S., Wu, Y., & Shang, Y. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00063 · Cited by 467
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Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246
“The same stress model 211 revealed long-lasting histone modi fi cations in the NAc after ELS.”
BackgroundMorel, C., Montgomery, S. E., Li, L., Cuttoli, R. D.-D., Teichman, E. M., Juarez, B., Tzavaras, N., Ku, S. M., Flanigan, M. E., Cai, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29155-1 · Cited by 178
Self-citationNeurobiological basis of stress resilience
Nestler, E. J., & Russo, S. J. (2024) · Neuron · doi:10.1016/j.neuron.2024.05.001 · Cited by 148
Self-citationImpact of Early Life Stress on Reward Circuit Function and Regulation
Hanson, J. L., Williams, A. V., Bangasser, D. A., & Peña, C. J. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.744690 · Cited by 133
Self-citationDissecting early life stress-induced adolescent depression through epigenomic approach
Ochi, S., & Dwivedi, Y. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01907-x · Cited by 94
Metadata
- Authors
- Kronman, H., Torres-Berrío, A., Sidoli, S., Issler, O., Godino, A., Ramakrishnan, A., Mews, P., Lardner, C. K., Parise, E. M., Walker, D. M., van der Zee, Y. Y., Browne, C. J., Boyce, B. F., Neve, R., Garcia, B. A., Shen, L., Peña, C. J., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Albert Einstein College of Medicine (US)
- New York State Psychiatric Institute (US)
- Oregon Health & Science University (US)
- Massachusetts General Hospital (US)
- University of Pennsylvania (US)
- Princeton University (US)
- Corresponding author
- Peña, Catherine J.
- Nestler, Eric J.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2021-03-15
- Volume
- 24
- Issue
- 5
- Pages
- 667-676
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8216773
- OpenAlex
- W3139250185
- Cited by
- 108
- References
- 62
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 21 · 2023: 26 · 2022: 15 · 2021: 12
- FWCI
- 12.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck
- Japan Agency for Medical Research and Development
- New York Academy of Sciences
- Brain and Behavior Research Foundation
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (K99DA042100, R00MH115096, P50MH096890, R01MH051399)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- early life stress, chronic social defeat stress, H3K79me2, histone modifications, DOT1L, KDM2B, D2 medium spiny neurons, nucleus accumbens, depression vulnerability, epigenetic regulation, transcriptional regulatory networks, DOT1L inhibitors, sex differences
- MeSH terms
- Animals, Gene Expression Regulation, Histones, Male, Neurons, Nucleus Accumbens, Histone-Lysine N-Methyltransferase, Stress, Psychological, Receptors, Dopamine D1, Receptors, Dopamine D2, F-Box Proteins, Mice, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases
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