Epigenetic Modifications of Major Depressive Disorder
Abstract
:1. Introduction
2. Genetics of Major Depression
3. Epigenetic Modifications and Depressive Disorders
3.1. DNA Methylation
3.2. Histone Modification
3.3. Non-Coding RNAs
4. Epigenetics Modifications in MDD Therapy
5. Future Perspectives
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Reference | Sample Characteristics | Study | Tissue | Diagnosis | Platform | Gene Associated | Potential Relevance of Gene in Depressive Disorders |
---|---|---|---|---|---|---|---|
Córdoba-Palomera et al. [49] 2015 | 17 MZ pairs Caucasian Spanish adult twins | Genome-wide DNA methylation | Peripheral blood | Anxious or depressive disorder | Illumina Infinium HumanMethylation450 Beadchip | WDR26 | Prospective blood transcriptomic marker for depression [11,50]. |
CACNA1C | Susceptibility factor for depressive psychopathology [11]. Methylation changes have been associated with risk factors for depressive disorders [51,52]. | ||||||
MAPK11 | Associated with depression phenotypes [53]. | ||||||
Sabunciyan et al. [54] 2012 | 39 individuals with MDD from Stanley Medical Research Institute | Genome-wide DNA methylation | Post-mortem frontal cortex | MDD | Comprehensive High-throughput Arrays for Relative Methylation (CHARM) | PRIMA1 | Encodes a protein that functions to organize AChE into tetramers, and to anchor AChE to neural cell membranes [55,56]. |
Numata et al. [57] 2015 | 29 Medication-free patients with MDD | Genome-wide DNA methylation | Peripheral leukocytes | MDD | Infinium HumanMethylation450 BeadChips | CAPRIN1 | Potential blood marker of major depressive disorder [58]. |
CITED2 | Differentially expressed in the mood disorder, associated with neurological or psychiatric diseases [40]. | ||||||
DGKH | Risk gene for bipolar disorder [59,66]. | ||||||
Januar et al. [65] 2015 | 183 patients with MDD >65 years-old | High-throughput DNA methylation profiling | Buccal tissue | MDD | Sequenom MassARRAY | BDNF | Promotes the proliferation, differentiation and survival of neurons, crucial for neural plasticity and cognitive function [64]. Potential biomarker of depression [65]. |
Nieratschker et al. [38] 2014 | 8 mothers and their infants with prenatal stressed conditions. 9 pregnant rats with prenatal stressed conditions | Genome-wide association | Peripheral leukocytes and refrontal cortex of adult rats | MDD | Methylated DNA immunoprecipitation (MeDIP) and pyrosequencing | MORC1 | Candidate gene for major depressive disorder related to early life stress in rodents, primates and humans [38]. Evokes a depression-like phenotype in mice [39]. |
Davies et al. [67] 2014 | 50 monozygotic twin pairs from the UK and Australia discordant for depression | Genome-wide DNA methylation | Whole blood and brain tissue samples | MDD | MeDIP-Sequencing | ZBTB20 | Important for the hormonal hippocampal function, crucial for the regionalization and volume of archicortex, playing a role in depression [68,69]. |
Reference | Sample Characteristics | Tissue | Diagnosis | Platform | Epigenetic Modification Evaluated | Gene and Histone Modification Associated | Main Findings |
---|---|---|---|---|---|---|---|
Cruceanu et al. [80] 2013 | Individuals with bipolar disorder type I (n = 13) or MDD (n = 18) and controls (n = 14) with no psychiatric history | Post-mortem prefrontal cortex (PCF) from Broadman Area (BA) 10 | BD or MDD | Chromatin immunoprecipitation (ChIP) and Quantitative real-time PCR | Histone modification | SYN2 H3K4me3 | H3K4me3 increase in MDD patients and correlated with gene expression of SYN2 [80]. |
Covington et al. [71] 2009 | C57BL/6J male mice with chronic social defeat stress (n = 6) and control mice (n = 10). Patients depress postmortem (n = 8) | Brain tissue | Depression | Immunohistochemistry, Western blot and Illumina MouseWG-8 V2.0 array | Histone modification | H3K14ac | Transiently decreased and then stably increased of H3K14ac in the NAc of mice after chronic social defeat stress, correlated with a reduction in HDAC2 levels [71]. |
Hobara et al. [78] 2010 | Mood disorder patients in a depressive and remissive state | Peripheral white cells | MDD and BD | Quantitative real-time PCR | Expression of HDACs | HDAC2 and HDAC5 | Gene expression of HDAC2 and HDAC5 were significantly increased in MDD patients in depressive state compare to controls subjects, while during remissive state, HDACs expression was comparable to controls subjects, suggesting a state-dependent alteration [78]. |
Iga et al. [79] 2007 | Patients diagnosed with MDD according to DSM-IV (n = 25) and controls (n = 25) | Peripheral leucocytes | MDD | Quantitative real-time PCR | Expression of HDACs | HDAC5 | HDAC5 mRNA levels were significantly higher in drug-free depressive patients than controls [79]. |
Renthal et al. [77] 2007 | Mice with chronic social defeat stress | Brain tissue | Depression | Immnunohistochemistry, ChIP and microarray | Histone modification and expression of HDACs | HDAC5 | HDAC5 expression was decrease in a model with social defeat stress, imipramine treatment increased HDAC5 expression [77]. |
Reference | Sample Characteristics | Tissue | Diagnosis | Platform | miRNAs Associated | Main Findings |
---|---|---|---|---|---|---|
Uchida et al. [94] 2008 | SH-SY5Y cells and Male rats Fisher 344 (F344) and Sprague-Dawley (SD) control with repeated restraint stress | Neuron cell lines Hypothalamic paraventricular nucleus | ------ | ----- | miR-18a | Overexpressed in repeated restraint stress model. Its expression inhibits translation of the glucocorticoid receptor in neuron cell culture. |
Vreugdenhil et al. [97,111] 2009 | NS1 cells | Neuron cell lines | ------ | Luciferase reporter assay | miR-18a and miR-124a | miR-18a and miR-124a decrease protein expression of glucocorticoid receptor by luciferase reporter assay in NS1 cells. |
Caputo et al. [101] 2011 | HeLa cells | Cervix epithelial cell line | Schizophrenia | Luciferase reporter assay | miR-132 and miR-182 | These miRNAs regulate the expression of BDNF by Allele-Specific Binding [101]. |
Smalheiser et al. [98] 2012 | Antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) | Tissue, prefrontal cortex (Brodmann Area 9) | Depression | PCR miltiplex | miR-142-5p, miR-137, miR-489, miR-148b, miR-101, miR-324-5p, miR-301a, miR-146a, miR-335, miR-494, miR-20b, miR-376a*, miR-190, miR-155, miR-660, miR-130a, miR-27a, miR-497, miR-10a, miR-20a, miR-142-3p | miRs significantly downregulated in the prefrontal cortex of depressed patients compared with normal controls, many of them implicated in cellular growth and differentiation and some of them showed high synaptic enrichment [98,99]. |
Belzeaux et al. [96] 2012 | 16 severe MDE patients and 13 matched controls | Peripheral blood mononuclear cells | Major depressive episode | Microarray SurePrint G3 Human GE 8 x 60 K | miR-107, miR-133a, miR-148a, miR-200c, miR-381, miR-425-3p, miR-494, miR-517b, miR-579, miR-589, miR-636, miR-652, miR-941, miR-1243 | miRs significantly deregulated between MDE patients and controls. These miRs help finding a gene combination useful to predict treatment response [96]. |
Bocchio-Chiavetto et al. [100] 2013 | 10 patients with MD, the sample was extracted before and after treatment | Blood | MDD | TaqMan Array Human MicroRNA A + B Cards Set v3.0 | UP: miR-130b*, miR-505*, miR-29b-2*, miR-26b, miR-22*, miR-26a, miR-664, miR-494, let-7d, let-7g, let-7e, let-7f, miR-629, miR-106b*, miR-103, miR-191, miR-128, miR-502-3p, miR-374b, miR-132, miR-30d, miR-500, miR-589, miR-183, miR-574-3p, miR-140-3p, miR-335, miR-361-5p. DOWN: miR-34c-5p and miR-770-5p | Associated with neuronal brain function, such as neuroactive ligand–receptor interaction, axon guidance, long-term potentiation and depression [100]. |
Li et al. [33] 2013 | 40 patients and 40 healthy controls | Serum | MDD | Real time PCR | miR-132 and miR-182 | The expression of these miRs was negatively correlated with BDNF expression [33]. |
Fan et al. [112] 2014 | 81 MDD patients and 46 healthy controls | Peripheral blood mononuclear cells | MDD | Affymetrix miRNA 3.0 array | miRNA-26b, miRNA-1972, miRNA-4485, miRNA-4498, and miRNA-4743 | Overexpressed in MDD patients, and would regulate pathways associated with nervous system and brain functions [112]. |
Wan et al. [113] 2015 | 1° cohort: 6 depressed and 6 control patients. 2° cohort: 32 MDD patients and 21 healthy individuals | Peripheral blood mononuclear cells | MDD | microRNA PCR Panel (V3.M) | let-7d-3p, miR-34a-5p, miR-221-3p, miR-451a | Potential MDD biomarkers [113]. |
Wang et al. [114] 2015 | 169 patients and 52 controls | Plasma | Depression | Serum/Plasma Focus microRNA PCR Panel | miR-144-5p | miR-144-5p levels are associated with depressive symptoms, and the detection of this miR in plasma could be a potential peripheral biomarker for pathologic processes related to depression [114]. |
Study | ClinicalTrials.gov Identifier | Status | Phase | Aims | Intervention | Condition | Publications |
---|---|---|---|---|---|---|---|
Paliperidone and lithium in the treatment of suicidality—treatment indication and epigenetic regulation (AFSP) | NCT01134731 | Completed | Phase 4 | To identify an efficient pharmacotherapy for the acute management of suicidality and the epigenetic regulation associated with the treatment. | Paliperidone and lithium | MDD Suicidality | Not provided |
Epigenetic regulation of brain-derived neurotrophic factor (BDNF) in major depression | NCT01182103 | Completed | ----- | To detect the associations between BDNF, DNA methylation, histone modification, depressive symptoms, suicidal behavior and antidepressant responses in MDD patients, check the correlation between blood BDNF protein and RNA and BDNF rs6265 gene, and discuss the possible mechanisms of epigenetic regulation of BDNF in Taiwanese MDD patients. | ----- | MDD | Not provided |
A neuroimaging and epigenetic investigation of antidepressants in depression | NCT00703742 | Completed | ----- | To find out the structural or functional effects of SSRI in MDD; to explore the DNA methylation status in depression; to find special abnormalities in depression secondary to other disease (autoimmune disease like systemic lupus erythematosus). | Escitalopram | Depression secondary to other disease | [128,129] |
miRNAs, suicide, and ketamine—plasma exosomal microRNAs as novel biomarkers for suicidality and treatment outcome | NCT02418195 | Recruiting participants | Phase 2 | To examine whether neural-derived exosomal miRNAs are differentially expressed that are specific to suicidal ideation or behavior, and which by affecting specific miRNA targets and pathways, are associated with suicidal behavior and response to ketamine. | ketamine | MDD | Not provided |
Add-On Study of MSI-195 (S-adenosyl-l-methionine, SAMe) for patients with major depressive disorder (MDD) | NCT01912196 | Ongoing | Phase 2 | To determine the efficacy and safety of 800 mg MSI-195 in reducing symptoms of depression in Major Depressive Disorder (MDD) patients with inadequate response to current antidepressant therapy. | MSI-195 and Placebo | MDD | Not provided |
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Saavedra, K.; Molina-Márquez, A.M.; Saavedra, N.; Zambrano, T.; Salazar, L.A. Epigenetic Modifications of Major Depressive Disorder. Int. J. Mol. Sci. 2016, 17, 1279. https://doi.org/10.3390/ijms17081279
Saavedra K, Molina-Márquez AM, Saavedra N, Zambrano T, Salazar LA. Epigenetic Modifications of Major Depressive Disorder. International Journal of Molecular Sciences. 2016; 17(8):1279. https://doi.org/10.3390/ijms17081279
Chicago/Turabian StyleSaavedra, Kathleen, Ana María Molina-Márquez, Nicolás Saavedra, Tomás Zambrano, and Luis A. Salazar. 2016. "Epigenetic Modifications of Major Depressive Disorder" International Journal of Molecular Sciences 17, no. 8: 1279. https://doi.org/10.3390/ijms17081279