The DOI matches its Crossref record; 251 of the 251 references it cites were found in a registry or an index.
The Molecular Basis of Depression: Implications of Sex-Related Differences in Epigenetic Regulation
Open accessAbstract
Major depressive disorder (MDD) is a leading cause of disability worldwide. Although the etiology and pathophysiology of MDD remain poorly understood, aberrant neuroplasticity mediated by the epigenetic dysregulation of gene expression within the brain, which may occur due to genetic and environmental factors, may increase the risk of this disorder. Evidence has also been reported for sex-related differences in the pathophysiology of MDD, with female patients showing a greater severity of symptoms, higher degree of functional impairment, and more atypical depressive symptoms. Males and females also differ in their responsiveness to antidepressants. These clinical findings suggest that sex-dependent molecular and neural mechanisms may underlie the development of depression and the actions of antidepressant medications. This review discusses recent advances regarding the role of epigenetics in stress and depression. The first section presents a brief introduction of the basic mechanisms of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs. The second section reviews their contributions to neural plasticity, the risk of depression, and resilience against depression, with a particular focus on epigenetic modulators that have causal relationships with stress and depression in both clinical and animal studies. The third section highlights studies exploring sex-dependent epigenetic alterations associated with susceptibility to stress and depression. Finally, we discuss future directions to understand the etiology and pathophysiology of MDD, which would contribute to optimized and personalized therapy.
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“Accumulating evidence suggests that female patients are more likely to exhibit promoter hypermethylation of stress-related genes, including NR3C1 and SLC6A4, which has been associated with increased vulnerability to depression and differential treatment response (Kawatake-Kuno et al., 2021).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Kawatake-Kuno et al., 2021
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Cited by
Sorted by citations
Li, H., Kawatake-Kuno, A., Inaba, H., Miyake, Y., Itoh, Y., Ueki, T., Oishi, N., Murai, T., Suzuki, T., & Uchida, S. (2024) · Neuron · doi:10.1016/j.neuron.2023.12.004 · Cited by 36
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RetractedSex Significantly Impacts the Function of Major Depression–Linked Variants In Vivo
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Identification of Specific Plasma miRNAs as Potential Biomarkers for Major Depressive Disorder
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Depression: epigenetics and epitranscriptomic modifications
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Depression and Cancer: The Inflammatory Bridge
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Gao, J., Wang, Q., Liu, J., Zheng, S., Liu, J., Gao, Z., & Zhu, C. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1564095 · Cited by 1
Sex significantly impacts the function of major depression-linked variants in vivoPreprint
Mulvey, B., Selmanovic, D., & Dougherty, J. D. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.01.466849 · Cited by 1
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Distinct prefrontal neuronal circuits determine repeated stress-induced behavioral styles in mice
Uchida, S. (2026) · Folia Pharmacologica Japonica · doi:10.1254/fpj.25040
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Comparative evaluation of two chronic stress models in zebrafish for advancing depression research
Tripathy, C., Dhaygude, S. S., Vijay, V., Mondal, A., Soren, K., Kumar, A. T. R., & Chakravarty, S. (2026) · Physiology & Behavior · doi:10.1016/j.physbeh.2026.115453
Metadata
- Authors
- Kawatake-Kuno, A., Murai, T., & Uchida, S.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Uchida, Shusaku
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2021-07-01
- Volume
- 14
- Pages
- 708004-708004
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC8282210
- OpenAlex
- W3182076372
- Cited by
- 23
- References
- 251
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 2
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, sex differences, epigenetic regulation, DNA methylation, histone modifications, non-coding RNA, neuroplasticity, stress, antidepressant response, depression resilience, depression vulnerability, personalized treatment
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