DNA Methyltransferases in Depression: An Update

Abstract

Depression is one of the most common psychiatric disorders affecting public health. Studies over the past years suggest that the methylations of some specific genes such as BDNF, SLC6A4, and NR3C1 play an important role in the development of depression. Recently, epigenetic evidences suggest that the expression levels of DNA methyltransferases differ in several brain areas including the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens in depression patients and animal models, but the potential link between the expression levels of DNA methylatransferases and the methylations of specific genes needs further investigation to clarify the pathogenesis of depression.

Keywords: DNA methylation; DNA methyltransferase; DNMT1; DNMT3A; DNMT3B; DNMT3L; depression; neurodevelopment.

Figure 1

An illustrative model of gene-environment interactions underlying depressive behaviors through NR3C1 methylation. ELA events send signals to neurons in amygdala, which then send signals to hypothalamus to activate the HPA axis to release GC. In a feedback loop, GC activates GR in hypothalamus and pituitary to inhibit the HPA axis activation; it also activates IEGs that increase the transcription of DNMTs, TFs, and ncRNAs, which together up-regulate the DNA methylation in the promoter of NR3C1, inhibiting the expression of GR. These serial signals transduction results in HPA axis hyperactivity and GR resistance, which may cause increased inflammation and imbalanced neurotransmitters, therefore the susceptibility of depression. The depression signs in patients include depressed mood, anhedonia, lack of motivation, psychomotor changes (agitation/retardation), psychotic changes (delusion, hallucination), and cognitive changes (verbal memory, working memory, executive function). The depression-like signs in animal models include anhedonia-like behavior, despair-like behavior, anxiety-like behavior, locomotor changes, and cognitive changes (–100). This is a reversible process. The depression signs can be treated by regaining the GR activity with drugs that interfere with DNA methylation or GR expression (, –96). ACTH, Adrenocorticotropic hormone; CH3, DNA methylation; CRH, Corticotropin-releasing hormone; DNMTs, DNA methyltransferases; ELA, early life adversity; GC, glucocorticoids; GR, glucocorticoid receptor; HPA, hypothalamic–pituitary–adrenal; IEGs, immediate early genes; ncRNA, non-coding RNA; TF, transcription factor.