Cited by 106Treatment of Major DepressionStress Responses and CortisolGenomics and Chromatin Dynamics

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Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors

Liu, Yongqing, Li, Minghua, Fan, Minghua, Song, Yan, Yu, Huajing, Zhi, Xiaojie, Xiao, Kuo, Lai, Shirong, Zhang, Jingliang, Jin, Xueqin, Shang, Yongfeng, Liang, Jing, Huang, Zhuo·2019·Biological Psychiatry

DOI 10.1016/j.biopsych.2018.11.025

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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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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: Liu, Yongqing
Li, Minghua
Fan, Minghua
Song, Yan
Yu, Huajing
Xiao, Kuo
Zhang, Jingliang
Jin, Xueqin
Shang, Yongfeng
Liang, Jing
Huang, Zhuo
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2019-04
Volume: 85
Issue: 8
Pages: 635-649
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2018.11.025
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Chromodomain Y-like Protein–Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors

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