Table 1.
TETs and 5hmC in different psychiatric disorders.
| Type of Psychiatric Disorders | Alterations in TETs/5hmC | Downstream Mechanisms/ Behavior Effects |
Brain Region/Cell Type | Sample | References |
|---|---|---|---|---|---|
| ASD | Increased TET1 expression, increased level of 5-hmC at the promoters of GAD1 and RELN, increased TET1 binding to target gene promoter regions | A significant increase in MeCP2-binding to the hyperhydroxymethylated promoter regions of GAD1 and RELN | Cerebella | ASD postmortem | [65] |
| Genome-wide 5hmC level decrease, mainly in gene regions and repetitive elements | DhMRs annotation revealed a significant overlap with known ASD genes (e.g. Nrxn1 and Reln) | Striatal | Cntnap2−/− mice model for ASD | [66] | |
| Specific set of DhMRs in young age group (<18) | Significant overlap between DhMRs-related genes and ASD risk genes | Cerebella | ASD postmortem | [67] | |
| SCZ | Increased TET1 level | Higher DNA demethylation at GAD67 and BDNF promoter regions | Prefrontal cortex | SCZ postmortem | [68,69,70] |
| Increased TET1, together with increased DNMT1 and decreased NRG1, ErbB4, BDNF | Combination of ErbB4, BDNF and TET1 as biomarkers for SCZ diagnosis | Blood samples | SCZ patients | [73] | |
| TET1 function deficiency/Genome-wide 5hmC decrease, especially in gene body region | Hyper-hydroxymethylation level in myelination genes, cell cycle genes and calcium transporter genes/SCZ like behavior | Oligodendrocyte lineage cells | Tet1 conditional knock out mice | [53] | |
| Depression | Genome-wide decreased 5-hmC level | 5-mC levels positively correlated with severity of depressive symptoms | Blood samples | BD or MDD patients | [77] |
| Significant decrease of 5-hmC level in older age group | MDD may curtail the rise in methylation levels during normal aging | Leukocyte in blood sample | MDD patients | [79] | |
| Increased 5hmC level in genes encoding myosin XVI and insulin-degrading enzymes | Target genes are abnormally expressed in depressed suicides | Prefrontal cortex | Depression postmortem | [80] | |
| Tet1 ablation | Produced antidepressant-like effects | NAc neurons | Selective Tet1 knockout | [81] | |
| Decreased TET1 | TET1 negatively regulates reward behavior in the NAc through extensive dynamic changes in 5hmC at response genes | NAc neurons | CSDS mouse model for depression | ||
| Anxiety disorders | Tet3 ablation | Dysregulated genes involved in glucocorticoid signaling pathway (HPA axis) and upregulation of immediate early genes in hippocampus/Increased anxiety-like behavior | Adult brain neurons | Tet3 conditional knock out mice | [87] |
| Increased expression of TET3 | TET3-REST (silencing transcription factor) binary complexes to CRH intron/Improve the stress response late in life | Hypothalamic paraventricular nucleus | Experienced acute heat stress mice model | [88] | |
| Disrupted 5hmC | Disrupted gene expression in stress-related targets (eg. Nr3c2, Nrxn1, Nfia, and Clip1)/Anxiety-like behaviors in adult female mice | Hypothalamus | Experienced early-life stress mice model | [89] |
Abbreviations: MeCP2: methyl-CpG binding protein 2, GAD1: glutamate decarboxylase 1, RELN: reelin, DhMRs: differentially hydroxymethylated regions, Nrxn1: Neurexin 1, GAD67: glutamic acid decarboxylase67, BDNF: brain-derived neutrophic factor, NRG1: Neuregulin1, DNMT1: DNA methyltransferases 1, BD: bipolar disorder, MDD: Major depressive disorder, NAc: nucleus accumbens, CSDS: chronic social defeat stress, CRH: corticotropin-releasing hormone, REST: silencing transcription factor.