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Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors
Abstract
Background Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. Methods We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. Results The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. Conclusions Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.
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“In the medial prefrontal cortex of mice vulnerable to chronic social defeat stress, histone crotonylation was inhibited. In contrast, chromodomain Y-like protein (CDYL), which acts as both a crotonyl-CoA hydratase and a histone methyllysine reader, was selectively upregulated.183”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [183]
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Metadata
- Authors
- Liu, Y., Li, M., Fan, M., Song, Y., Yu, H., Zhi, X., Xiao, K., Lai, S., Zhang, J., Jin, X., Shang, Y., Liang, J., & Huang, Z.
- Affiliations
- Peking University (CN)
- State Key Laboratory of Natural and Biomimetic Drugs (CN)
- Capital Medical University (CN)
- Corresponding author
- Liang, Jing
- Huang, Zhuo
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 85
- Issue
- 8
- Pages
- 635-649
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2903522465
- Cited by
- 106
- References
- 56
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 13 · 2023: 18 · 2022: 18 · 2021: 16 · 2020: 7 · 2019: 8
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of China (2017YZ0072839, 2015CB559200)
- National Natural Science Foundation of China (31871083, 81371432, 81572771, 91219201, 81130048)
- Beijing Natural Science Foundation (Grant No. 7182087)
- Peking University Health Science Center
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone crotonylation, major depressive disorder, chronic social defeat stress, social avoidance, anhedonia, medial prefrontal cortex, prelimbic cortex, VGF, H3K27me3, synaptic plasticity, epigenetic regulation, stress vulnerability
- MeSH terms
- Acylation, Adenoviridae, Animals, Depressive Disorder, Major, Major Depressive Disorder, Genetic Vectors, Histones, Hydro-Lyases, Male, Methylation, Nerve Growth Factors, Neuronal Plasticity, Stress, Psychological, Up-Regulation, Prefrontal Cortex, Epigenesis, Genetic, Acyl-CoA Dehydrogenases, Mice, Rats, Gene Knockdown Techniques, Co-Repressor Proteins
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