Copyright
©The Author(s) 2022.
World J Psychiatry. Sep 19, 2022; 12(9): 1150-1168
Published online Sep 19, 2022. doi: 10.5498/wjp.v12.i9.1150
Published online Sep 19, 2022. doi: 10.5498/wjp.v12.i9.1150
Table 1 DNA methylation studies on depressed subjects, also associated with suicidality and life adversities
| Gene (region) | Alteration | Subjects and collected tissue | Ref. |
| NR3C1 1-F and FKBP5 intron 7 promoter | ↑ DNA methylation at NR3C1 1-F, without significant differences at any of the measured individual CpG site in depressed patients. Association in salivary cortisol level and DNA methylation. ↑ DNA methylation in NR3C1 1-F at CpG 38 site in depressed patients, with early life adversity. No differences in FKBP5 intron 7 promoter | 33 depressed patients (24 females, 9 males), 34 controls (21 females, 13 males). Whole blood and saliva | Farrell et al[67], 2018 |
| MAOA and NR3C1 exon 1-F | ↓ DNA methylation at MAOA’s first exon/intron junction; significantly ↓ at CpG 8 site from the intron region. ↑ DNA methylation at NR3C1 1-F’s promoter and exon in individuals experienced early parental death; significant ↑ at CpG 35 and 10.11 (sites close to NGFI-A binding site) | 82 (for MAOA gene) and 93 (for NR3C1 1-F gene) depressed females, victims of early-life adversity and 92 or 83 controls. Saliva | Melas et al[35], 2013 |
| BDNF, NR3C1, and FKBP5 | Significant alteration in DNA methylation at 9 sites in BDNF gene body, at 6 sites in NR3C1 promoter region, and at 4 sites in FKBP5 gene body, 3’UTR and promoter | 94 maltreated and 96 non-traumatized children. Saliva | Weder et al[68], 2014 |
| BDNF exon I | ↓ DNA methylation; differences at loci 87, 88 and 92–94, located within the CpG island region on the promoter of the exon I | 360 depressed patients (32 females, 328 males). Saliva | Song et al[69], 2014 |
| BDNF promoter between –694 and –577 relative to the transcriptional start site (12 CpG sites). SLC6A4 promoter adjacent to exon 1a between –479 and –350 relative to the transcriptional start site (10 CpG sites) | Depressed mood in 2nd trimester associated with ↓ DNA methylation at maternal SLC6A4 promoter methylation status. ↓ DNA methylation at SLC6A4 promoter in infants, from mothers with higher depressed mood during 2nd trimester. No difference in BDNF gene | 82 female and male infants exposed to prenatal maternal stress–33 mothers treated with SRI and 49 mothers not treated with SRI. Blood | Devlin et al[70], 2010 |
| NR3C1 exon 1-F and BDNF promoter IV | ↑ DNA methylation within NR3C1 1-F gene (male infants). ↓ DNA methylation within BDNF promoter IV region (female and male infants) | 20 female and male infants exposed to prenatal maternal stress and 37 controls. Buccal tissue | Braithwaite et al[71], 2015 |
| NR3C1 exon 1-F | Depressed mood in 2nd trimester associated with ↑ DNA methylation of CpG 2 site (relative to translational start site) at NR3C1 exon 1-F in infants. Depressed mood in 3d trimester associated with ↑ DNA methylation of CpG 2 and CpG 3 site (relative to translational start site) at NR3C1 exon 1-F in infants | 46 depressed females (33 treated with SRI and 13 not medicated), 36 controls, and their infants. Blood | Oberlander et al[72], 2008 |
| BDNF, NR3C1, CRHBP, CRHR1, FKBP5 promoter | Hypermethylated BDNF, NR3C1, CRHBP and FKBP5 promoter. mRNA down regulation of BDNF, NR3C1, FKBP5 and CRHBP in MDD-suicidal ideation group | 15 females and 9 males with MDD (14 with and 10 without suicidal ideation) and 20 controls (14 females and 6 males). PBMC | Roy et al[73], 2017 |
| BDNF exon I promoter | ↑ percentage of methylated reference values | 207 female and male MDD patients and 278 controls. PBMC | Carlberg et al[58], 2014 |
| BDNF exon I promoter | ↑ at CpG 1, CpG 3 and CpG 5 site, ↓ BDNF serum level | 49 female and male MDD patients and 57 controls. Blood | Schröter et al[74], 2020 |
| BDNF exon I and IV promoter | ↑ methylation at CpG site 3 of promoter IV | 251 female and male MDD patients aged 65 > and 773 controls. Buccal tissue | Januar et al[75], 2015 |
| BDNF exon IX | Changes in DNA methylation; ↑ at CpG site 217, ↓ at CpG site 327, and 362. ↓ BDNF level and mRNA levels | 51 MDD patients (35 females and 16 males) and 62 controls (39 females and 23 males). Venous blood | Hsieh et al[60], 2019 |
| BDNF upstream of exon I and IV | Changes in DNA methylation within CpG exon I promoter | 20 MDD patients (12 females and 8 males) and 18 controls (8 females and 10 males). Blood | Fuchikami et al[76], 2011 |
| MYO16 and IDE | ↑ 5hmc in one CpG position of MYO16 and two CpG positions of IDE in the PFC. ↑ gene expression of MYO16. ↓ gene expression of IDE | 19 depressed male suicide victims and 19 controls. Brain tissue (PFC; inferior frontal gyrus) | Gross et al[77], 2017 |
| GABAA receptor α1 subunit promoter | ↑ DNA methylation of the CpG 2 and CpG 4 site (500 bp from transcriptional start site). ↑ DNMT-3B expression in FPC. ↓ expression of DNMT1 mRNA and ↑ expression of DNMT3b mRNA in FPC. ↓ expression of DNMT3b and DNMT1 mRNA in AMG | 10 male suicide victims and 10 controls. Brain tissue (FPC, AMG) | Poulter et al[78], 2008 |
| SLC6A4 promoter | ↑ mean methylation level | 28 MDD patients (20 females and 8 males) and 29 controls (21 females and 8 males). Blood | Iga et al[79], 2016 |
| NR3C1 exon 1 promoter | ↑ methylation at CpG 30 and 32 site. ↓ expression of total NR3C1 mRNA and NR3C1-1F mRNA in suicide victims without childhood abuse and control group | 12 suicide victims with traumatic childhood experience, 12 suicide victims without traumatic childhood experience, and 12 controls. Brain tissue (HPC) | McGowan et al[80], 2009 |
Table 2 Histone tail modifications studies on depressed suicide victims
| Gene (region)/histone tail modification | Alteration | Subjects and collected tissue | Ref. |
| BDNF, H3K9/14ac, H3K27me2 | ↓ H3K9/14ac, ↑ HDAC2, ↑ HDAC3, ↑ H3K27me2, ↓ BDNF in HPC and NAc. ↑ Sin3a in HPC | 14 suicide victims (5 females and 9 males) without psychiatric diagnosis and 8 controls (3 females and 5 males). Brain tissue (HPC, NAc, and FCx; BA10) | Misztak et al[53], 2020 |
| H3K4me3 | ↑ In H3K4me3 at promoter of SYN2. ↑ expression SYN2b; no changes in SYN2a expression | 7 females and 11 males with MDD suicide victims and 14 controls (3 females and 12 males). Brain tissue (PFC; BA10) | Cruceanu et al[81], 2013 |
| H3K14ac | ↑ H3K14ac. ↓ HDAC2 mRNA expression | 8 depressed females and males. Brain tissue (NAc) | Covington et al[11], 2009 |
Table 3 MicroRNA expression studies on depressed suicide victims
| miRNAs | Alteration | Subjects and collected tissue | Ref. |
| miR-218 | ↓ miR-218 and ↑ DCC in PFC | 11 male suicide victims with MDD and 12 male controls. Brain tissue (PFC; BA44) | Torres-Berrío et al[82], 2017 |
| ↓ 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. ↓ by 30% or more: miR-211, miR-511, miR-424, miR-369-3p, miR-597, miR-496, miR-517c, miR-184, miR-34a, miR-34b-5p, miR-24-1*, miR-594, miR-34c-5p, miR-17*, miR-545, miR-565 | Globally ↓ miRNAs expression by 17% on average in depressed subjects. miR-148b targets DNMT3B, protein level was upregulated in depressed subjects. miR-34a targets BCL2, protein level was downregulated in depressed subjects | 18 suicide victims (2 females and 16 males) with depression and 17 male control subjects. Brain tissue (PFC; BA9) | Smalheiser et al[83], 2012 |
| miR-1202 | ↓ miR-1202, and ↑ GRM4 mRNA expression in BA44 | 25 suicide victims (2 females and 23 males) with MDD and 29 control subjects (4 females and 25 males). Brain tissue (PFC; BA44). 32 subjects with MDD (24 females and 10 males) and 18 control subjects (8 females and 10 males). Blood | Lopez et al[84], 2014 |
| miR-30e | ↑ miR-30e, ↓ ZDHHC21 protein | 16 suicide victims (7 females and 9 males) with MDD and 16 controls (6 females and 10 males). Brain tissue (PFC; BA9) | Gorinski et al[85], 2019 |
| miR-19a-3p | ↑ miR-19a-3p (might be involved in the modulation of TNF-α signaling) | 12 depressed patients with severe suicidal ideation, 12 control subjects. PBMC | Wang et al[86], 2018 |
| More than 10 miRNAs | ↑ miR-17-5p, miR-20b-5p, miR-106a-5p, miR-330-3p, miR-541-3p, miR-582-5p, miR-890, miR-99b-3p, miR-550-5p, miR-1179. ↓ miR-409-5p, let-7g-3p, miR-1197 | 9 depressed suicide victims (3 females and 6 males) and 11 control subjects (2 females and 9 males). Brain tissue (locus coeruleus) | Roy et al[37], 2017 |
| miR-326 | ↓ miR-326, ↑ UCN1 | 5 male suicide victims with MDD and 8 male controls. Edinger-Westphal nucleus | Aschrafi et al[87], 2016 |
| 10 miRNAs tested | ↑ miR-34c-5p, miR-139-5p, miR-195, miR-320c. ↓ SAT1 and SMOX mRNA | 15 male suicide victims with MDD and 16 male control subjects. Brain tissue (BA44) | Lopez et al[88], 2014 |
| miR-204-5p, miR-320b, miR-323a-3p, miR-331-3p | ↑ miR-204-5p, miR-320b, miR-323a-3p, miR-331-3p in ACC and lateral habenula. miR-323a-3p influences the expression of ERBB4. Decreased expression in ACC and lateral habenula | 39 suicide victims with MDD (13 females and 26 males) and 41 control subjects (10 females and 31 males) for ACC region. 24 suicide victims with MDD (10 females and 14 males), 13 control subjects (5 females and 8 males) for lateral habenula. Brain tissue (ACC and lateral habenula) | Fiori et al[89], 2021 |
| 171 miRNA differently expressed | ↑ 117 miRNAs. ↓ 54 miRNAs | 22 (10 females and 12 males) MDD subjects (10 died by suicide, 12 died from cause other than suicide) and 25 control subjects (10 females and 15 males). Brain tissue (ACC) | Yoshino et al[90], 2020 |
| miR-128-3p | ↑ miR-128-3p. ↓ WNT5B, DVL1 and LEF1 | 20 MDD (10 females and 10 males) subjects and 22 control subjects (9 females and 13 males). Brain tissue (AMG) | Roy et al[91], 2020 |
| miR-16 | ↓ miR-16 | 36 MDD (21 females and 15 males) subjects and 30 controls (17 females and 13 males). CSF | Song et al[92], 2015 |
Table 4 Epigenetic (DNA methylation, histone tail modifications, and microRNAs) studies on animal models of depressive disorder
| Epigenetic modification | Gene (region)/histone tail modification/miRNA | Alteration | Organism and collected tissue | Ref. |
| DNA methylation | Crf promoter of exon 1 and intronic region between exon 1 and exon 2 (relative to exon 1 start site) | Overall ↑ DNA methylation, and specific ↑ in CpG –147 and CpG –101 site of the Crf gene in stressed female rats in the PVN. No changes in male rats. ↓ DNA methylation in CpG –15 (male and female rats), ↓ DNA methylation in CpG –226, CpG –55 and ↑ in CpG +485 and CpG +494 (male rats) and ↓ DNA methylation in CpG –95 site (female rats) in BNST. ↑ DNA methylation in CpG –232 and CpG –226 (male rats), ↓ CpG –226 and CpG +535 (female) in the CeA | Male and female Wistar-R Amsterdam rats; sacrificed 2 h after stress. Brain tissue (PVN, BNST, CeA) | Sterrenburg et al[93], 2011 |
| DNA methylation | Crf promoter (relative to exon 1 start site) | Chronic social stress induced ↑ DNA methylation in Crf promoter region at CpG site –226 and ↓ DNA methylation level in intronic region of the gene Crf in the PVN. Long term effect of social defeat in mice susceptible to social defeat: ↑ in Crf mRNA levels in PVN and ↓ DNA methylation level at CpG –226, –101, –95, and –79 | Chronically stressed adult mice C57BL/6. Brain tissue (PVN) | Elliott et al[94], 2010 |
| DNA methylation and histone tail modification | Gdnf | ↑ DNA methylation at CpG site 2. ↓ H3ac in NAc of BALB mice and C57BL/6 mice. C57BL/6 mice had higher H3ac and higher Gdnf expression | BALB/c mice with maladaptive response to stressful stimuli and stress resilient strain C57BL/6. Brain tissue (NAc) | Uchida et al[95], 2011 |
| Histone tail modification | H3K14ac | ↓ H3K14ac 1 h after final stress. ↑ H3K14ac 24 h and 10 d after final stress. ↓ Hdac2 mRNA expression 24 h and 15 d after final stress in NAc | Chronically social defeated adult male mice C57BL/6J. Brain tissue (NAc). | Covington et al[11], 2009 |
| Histone tail modification | H3K14ac | H3K14ac ↑ after 24 h and ↓ at longer time in HPC. H3K14ac ↑ after 1 h and 24 h, no changes 10 d and longer in AMG | Chronically social defeated adult male mice C57/BL6J. Brain tissue (HPC and AMG) | Covington et al[96], 2011 |
| Histone tail modification | Bdnf exon IV, H3ac, H4ac | ↓ exon IV Bdnf mRNA. ↓ H3ac and H4ac. ↑ MeCP2 levels. ↑ Hdac mRNA | Rats (early life adversity induced by maternal separation). Brain tissue (HPC) | Seo et al[97], 2016 |
| Histone tail modification | Bdnf III and IV promoter, H3K27me2 | ↑ H3K27me2 at promoter Bdnf III and IV. ↓ total Bdnf mRNA. No change at H3K9me2 | Chronic social defeat stress mice. Brain tissue (HPC) | Tsankova et al[62], 2006 |
| Histone tail modification | H3K9me2 | ↑ H3K9me2 in HPC and mPFC. ↓ Bdnf expression in HPC and mPFC | Wistar rats exposed to maternal separation and chronic unpredicted mild stress. Brain tissue (HPC and mPFC) | Jiang et al[98], 2021 |
| Histone tail modification | H3K4me3, H3K9me3, H3K27me3 | Acute restrain stress: ↑ in H3K9me3 in CA1 and DG; no changes in CA3; ↓ in H3K27me3 in DG and CA1; not significantly altered in CA3. No significant changes for H3K4me3. Subchronic 7-d restraint stress: The basal level of H3K9me3 on day 7 increased in DG, CA1 and CA3. ↓ in H3K9me3 in CA1, CA3 and DG. ↓ in H3K27me3 in DG | Adult male Sprague–Dawley rats (acute stress/7 d restraint stress). Brain tissue (HPC parts: DG, CA1, CA3) | Hunter et al[99], 2009 |
| miRNA | miR Let-7a-1, miR-9, miR-25a/b | ↑ miR Let-7a-1, miR-9, miR-25a/b after acute stress in FCx. No changes in HPC | Male CD1 mice with induced acute or repeated stress. Brain tissue (FCx and HPC) | Rinaldi et al[100], 2010 |
| miRNA | miR-218 | ↓ miR-218 and ↑ DCC in PFC | Chronically social defeated adult male mice C57BL/6. Brain tissue (mPFC) | Torres-Berrío et al[82], 2017 |
| miRNA | miR-16 | ↑ miR-16. ↓ Bdnf mRNA | Sprague-Dawley rats exposed to maternal deprivation. Brain tissue (HPC) | Bai et al[101], 2012 |
| miRNA | 342 miRNAs differently expressed (response to gestational stress) and 336 miRNAs differently expressed in offspring (response to prenatal stress) | ↑ 147 miRNAs and ↓ 195 miRNAs in FCx of female rats. ↑ 205 miRNAs and ↓ 131 miRNAs in offspring | Stress induced through pregnant female Long-Evans rats. Offspring (decapitated 1 to 5 h after parturition). Brain tissue (FCx) | Zucchi et al[102], 2013 |
| miRNA | AMG: 10 miRNAs under acute stress and 28 after chronic stress; HPC CA1: 16 after acute stress and 22 after chronic stress | The overlap: ↑ miR Let-7a-1 in AMG affected by acute and chronic stress. ↑ miR-376b and miR-208, ↓ miR-9 in HPC by acute and chronic stress. Other changes are unique to acute/chronic stress or brain region analyzed | Adult male rats with induced acute or chronic stress. Brain tissue (AMG, HPC CA1 region) | Meerson et al[103], 2010 |
| miRNA | miR-124a, miR-18a, miR-511 | ↑ miR-124a, miR-18a in PFC and HPC persistently. ↓ miR-511 in PFC (in adult rats experienced CUMS) | Adolescent male Wistar rats were stressed with CUMS. Brain tissue (PFC and HPC) | Xu et al[104], 2019 |
Table 5 Histone deacetylase classification and localization
| HDAC category | HDAC class | HDAC type | Localization |
| Zinc-dependent HDACs | Class I | HDACs 1, 2, 3, 8 | Localized in nucleus |
| Class II | HDACs 4, 5, 7, 9, 10 | Pass between nucleus and cytoplasm | |
| HDAC6 | Localized in the cytoplasm | ||
| Class IV | HDAC11 | ||
| NAD-dependent SIRTs | Class III | SIRTs 1, 2, 6 and 7 | Localized in the nucleus |
| SIRTs 3, 4 and 5 | Localized in the mitochondria |
- Citation: Šalamon Arčan I, Kouter K, Videtič Paska A. Depressive disorder and antidepressants from an epigenetic point of view. World J Psychiatry 2022; 12(9): 1150-1168
- URL: https://www.wjgnet.com/2220-3206/full/v12/i9/1150.htm
- DOI: https://dx.doi.org/10.5498/wjp.v12.i9.1150