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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Items 201–251 of 251
Epigenetics: A missing link between early life stress and depression
Juruena, M. F., Gadelrab, R., Cleare, A. J., & Young, A. H. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110231 · Cited by 80
Choi, M., Lee, S. H., Wang, S. E., Ko, S. Y., Song, M., Choi, J.-S., Kim, Y.-S., Duman, R. S., & Son, H. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1513913112 · Cited by 79
de Carvalho-Netto, E. F., Myers, B., Jones, K., Solomon, M. B., & Herman, J. P. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.01.024 · Cited by 77
Global long non-coding RNA expression in the rostral anterior cingulate cortex of depressed suicides
Zhou, Y., Lutz, P.-E., Wang, Y. C., Ragoussis, J., & Turecki, G. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0267-7 · Cited by 77 · cited 2×
“expressed lncRNAs as well as their differentially expressed overlapping and antisense protein-coding genes in the rostral anterior cingulate cortex (Zhou et al., 2018).”
BackgroundIn vivo locus-specific editing of the neuroepigenome
Yim, Y. Y., Teague, C. D., & Nestler, E. J. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0334-y · Cited by 76
Tian, F., Hu, X., Wu, X., Jiang, H., Pan, H., Marini, A. M., & Lipsky, R. H. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06058.x · Cited by 75
ENĂTESCU, V. R., Papavă, I., Enătescu, I., Antonescu, M., Anghel, A., Șeclăman, E. P., Sîrbu, I. O., & Marian, C. (2016) · Psychiatry Investigation · doi:10.4306/pi.2016.13.5.549 · Cited by 74
Shulha, H. P., Cheung, I. K., Guo, Y., Akbarian, S., & Weng, Z. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003433 · Cited by 73
State-dependent changes in the expression of DNA methyltransferases in mood disorder patients
Higuchi, F., Uchida, S., Yamagata, H., Otsuki, K., Hobara, T., Abe, N., Shibata, T., & Watanabe, Y. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.04.008 · Cited by 73
Circulating microRNA 134 sheds light on the diagnosis of major depressive disorder
Zhang, H., Liu, X., Chen, J., Cheng, K., Bai, S., Zheng, P., Zhou, C., Wang, W., Wang, H., Zhong, L., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0773-2 · Cited by 73
Gross, J. A., Pacis, A., Chen, G., Megan, D., Lutz, P.-É., Barreiro, L. B., & Turecki, G. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.93 · Cited by 72
Yoshino, Y., Roy, B., & Dwivedi, Y. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00861-y · Cited by 70
Weiser, M. J., Foradori, C. D., & Handa, R. J. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.098 · Cited by 66
Down-Regulation of SIRT1 Gene Expression in Major Depressive Disorder
Luo, X.-J., & Zhang, C. (2016) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2016.16040394 · Cited by 66
Brain, networks, depression, and more
Leistedt, S., & Linkowski, P. (2012) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.011 · Cited by 63
Fan, C., Zhu, X., Song, Q., Wang, P., Liu, Z., & Yu, S. Y. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.009 · Cited by 63
X chromosome inactivation in the cycle of life
Barakat, T. S., & Gribnau, J. H. (2012) · Development · doi:10.1242/dev.069328 · Cited by 58
State-dependent changes in the expression of DNA methyltransferases in mood disorder patients
Higuchi, F. (2013) · Medical Entomology and Zoology · Cited by 57
Liang, X., Deng, W., Liu, Y., Liang, Y., Fan, Z.-M., Gu, X., Liu, J., Sha, A., Diao, H., & Yang, Z. (2016) · Scientific Reports · doi:10.1038/srep22744 · Cited by 57
MiR-221 is involved in depression by regulating Wnt2/CREB/BDNF axis in hippocampal neurons
Lian, N., Niu, Q., Lei, Y., Li, X., Li, Y., & Song, X. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1556060 · Cited by 57
Ji, B., Higa, K. K., Kelsoe, J. R., & Zhou, X. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.06.012 · Cited by 55
Peay, D. N., Saribekyan, H. M., Parada, P. A., Hanson, E. M., Badaruddin, B. S., Judd, J. M., Donnay, M. E., Padilla-Garcia, D., & Conrad, C. D. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112519 · Cited by 46
Age-associated decrease in global DNA methylation in patients with major depression
Lin, P., Tseng, P., Lee, Y. Z., Hung, C., Lung, F., Chen, C., & Chong, M. (2014) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s71997 · Cited by 45
Wang, Q., Roy, B., & Dwivedi, Y. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0448-z · Cited by 44
He, C., Bai, Y., Wang, Z., Fan, D., Wang, Q., Liu, X., Zhang, H., Zhang, H., Zhang, Z., Yao, H., et al. (2021) · NeuroImage · doi:10.1016/j.neuroimage.2020.117428 · Cited by 44
Ortiz, J. B., Taylor, S. B., Hoffman, A. N., Campbell, A. N., Lucas, L., & Conrad, C. D. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.12.051 · Cited by 42
Cui, X., Niu, W., Kong, L., He, M., Jiang, K., Chen, S., Zhong, A., Li, W., Lu, J. Z., & Zhang, L. (2017) · Brain and Behavior · doi:10.1002/brb3.711 · Cited by 42
Altered expression of long noncoding RNAs in patients with major depressive disorder
Seki, T., Yamagata, H., Uchida, S., Chen, C., Kobayashi, A., Kobayashi, M., Harada, K., Matsuo, K., Watanabe, Y., & Nakagawa, S. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.07.004 · Cited by 42
Self-citationColey, E. J. L., Demaestri, C., Ganguly, P., Honeycutt, J. A., Peterzell, S., Rose, N., Ahmed, N., Holschbach, M., Trivedi, M. S., & Brenhouse, H. C. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00101 · Cited by 41
Liu, J., Hu, P., Qi, X., Meng, F., Kalsbeek, A., & Zhou, J. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02123.x · Cited by 39
Autobiographical memory dysfunctions in depressive disorders
Talarowska, M., Berk, M., Maes, M., & Gałecki, P. (2016) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12370 · Cited by 38
Roy, B., Wang, Q., & Dwivedi, Y. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy010 · Cited by 38
Manners, M. T., Brynildsen, J. K., Schechter, M. S., Liu, X., Eacret, D., & Blendy, J. A. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.06.035 · Cited by 38
Synaptically Localized Transcriptional Regulators in Memory Formation
Uchida, S., & Shumyatsky, G. P. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.07.023 · Cited by 33
Zeng, Y., Navarro, P., Shirali, M., Howard, D. M., Adams, M. J., Hall, L. S., Clarke, T., Thomson, P. A., Smith, B. H., Murray, A. D., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.012 · Cited by 32
Webb, A., Papp, A. C., Curtis, A., Newman, L. C., Pietrzak, M., Seweryn, M. T., Handelman, S. K., Rempała, G. A., Wang, D., Graziosa, E., et al. (2015) · BMC Genomics · doi:10.1186/s12864-015-2207-8 · Cited by 31
Targeting 2‐arachidonoylglycerol signalling in the neurobiology and treatment of depression
Silveira, K. M., Wegener, G., & Joca, S. R. L. (2021) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13595 · Cited by 30
Palma-Gudiel, H., Peralta, V., Deuschle, M., Navarro, V., & Fañanás, L. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.09.002 · Cited by 28
Punzi, G., Ursini, G., Viscanti, G., Radulescu, E., Shin, J. H., Quarto, T., Catanesi, R., Blasi, G., Jaffe, A. E., Deep‐Soboslay, A., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.11.002 · Cited by 28
Histone Serotonylation: Can the Brain Have “Happy” Chromatin?
Anastas, J. N., & Shi, Y. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.04.017 · Cited by 27
Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress
Papale, L. A., Li, S., Madrid, A., Zhang, Q., Chen, L., Chopra, P., Jin, P., Keleş, S., & Alisch, R. S. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.08.014 · Cited by 26
Thompson, W. A., & Vijayan, M. M. (2021) · Environmental Pollution · doi:10.1016/j.envpol.2021.116535 · Cited by 26
Sex-specific effects of social defeat stress on miRNA expression in the anterior BNST
Luo, P. X., Manning, C., Fass, J. N., Williams, A. V., Hao, R., Campi, K. L., & Trainor, B. C. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113084 · Cited by 24
Hill, J., Pickles, A. R., Wright, N., Quinn, J. P., Murgatroyd, C., & Sharp, H. M. (2019) · Cells · doi:10.3390/cells8090943 · Cited by 23
Distinct epigenetic signatures between adult-onset and late-onset depression
Yamagata, H., Ogihara, H., Matsuo, K., Uchida, S., Kobayashi, A., Seki, T., Kobayashi, M., Harada, K., Chen, C., Miyata, S., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-81758-8 · Cited by 23
Sakai, Y., Li, H., Inaba, H., Funayama, Y., Ishimori, E., Kawatake-Kuno, A., Yamagata, H., Seki, T., Hobara, T., Nakagawa, S., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102504 · Cited by 20
First robust genetic links to depression emerge
Ledford, H. (2015) · Nature · doi:10.1038/523268a · Cited by 16 · cited 2×
“One of the first SNPs identified as related to depression by GWAS was located in the SIRT1 gene (Ledford, 2015), which encodes a type III HDAC.”
BackgroundHirata, T., Otsuka, I., Okazaki, S., Mouri, K., Horai, T., Boku, S., Takahashi, M., Ueno, Y., Sora, I., Shirakawa, O., et al. (2019) · Psychiatry Research · doi:10.1016/j.psychres.2019.06.002 · Cited by 16
Genomics and the future of psychopharmacology: MicroRNAs offer novel therapeutics
Gurwitz, D. (2019) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2019.21.2/dgurwitz · Cited by 12
Talebizadeh, Z., Shah, A., & DiTacchio, L. (2019) · Autism Research · doi:10.1002/aur.2116 · Cited by 11
Combined Pharmacotherapy and Psychological Treatment for Depression: A Systematic Review
Pampallona, S., Bollini, P., Tibaldi, G., Kupelnick, B., & Munizza, C. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.7.714 · Cited by 5
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
Kawatake-Kuno, A., Li, H., Inaba, H., Hikosaka, M., Ishimori, E., Ueki, T., Garkun, Y., Morishita, H., Narumiya, S., Oishi, N., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.01.023 · Cited by 31
Inaba, H., Li, H., Kawatake-Kuno, A., Dewa, K., Nagai, J., Oishi, N., Murai, T., & Uchida, S. (2023) · Science Advances · doi:10.1126/sciadv.ade5397 · Cited by 32
Kawatake-Kuno, A., Murai, T., & Uchida, S. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.749180 · Cited by 26
Zha, B., Cai, A., Yu, H., & Wang, Z. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.04.139 · Cited by 17
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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