Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Abstract

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30-40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.

Fig. 1

Overview of the role of epigenetic processes on the pathophysiology of stress-related disorders. Environmental factors, including early life stress, childhood trauma, and stressful life events in adulthood contribute to the development of stress-related disorders through direct epigenetic regulation or gene-by-environment interactions. Epigenetic mechanisms include chromatin structure changes, histone modifications, DNA modification, noncoding RNA changes, and RNA modifications. These epigenetic processes play crucial roles in different aspects of the pathophysiology of stress-related disorders

Fig. 2

DNA methylation is involved in the progression of MDD and stress-related disorders. DNA methylation is a biological process by which methyl groups are added to the DNA at position 5′ in cytosine (5mC), which is mainly found at CpG dinucleotides. In contrast to DNA methylation, which is set up by methyltransferases (DNMT3A and DNMT3B) and maintained by DNMT1, 5mC is oxidized to 5hmC by the ten-eleven translocation (TET) family of dioxygenase proteins. In successive steps, TET enzymes further hydroxylate 5hmC to 5fC and then 5caC, which are recognized and removed by TDG, generating an unmodified cytosine. Many clinical and animal studies have examined DNA methylation of genes involved in multiple biological pathways. 5mC methylation at position 5′ in the cytosine, DNMT DNA methyltransferase, TET ten-eleven translocation, 5hmC 5-hydroxymethylcytosine, 5fC 5-formylcytosine, 5caC 5-carboxylcytosine, TDG thymine-DNA glycosylase

Fig. 3

Different types of histone modification changes in different brain regions in stressed animals and depressed humans. a Animal models and behavior analyses for studying the relationship between stress vulnerability to epigenetic changes and depression. Recent studies using animal models show brain region-specific histone modification changes. The NAc^,,,,, and hippocampus^,,,,, are the most studied brain regions for histone modification, with both consistent and conflicting findings across different studies. Different types of histone modification are also observed in other brain regions, such as the prefrontal cortex. b Histone modification changes based on human postmortem tissue^,,, and peripheral blood, collected in both cases from depressed individuals^,. c Chemical reactions involved in histone acetylation and methylation. NAc nucleus accumbens, CoA crotonyl-coenzyme A, HDAC histone deacetylases, HAT histone acetyl transferases, SAM S-adenosyl methionine, HMT histone methyltransferases, HDM histone demethylases, SAH S-adenosyl homocysteine, α-KG α-ketoglutarate. ↑ Increased changes compared with controls; ↓ decreased changes compared with controls; ↑↓ both increased and decreased changes were reported across different studies

Fig. 4

Noncoding RNA in depression: generation, mechanisms of function, and effects. DNA constitutes an essential part of the human genome and contributes to the formation of noncoding RNA after transcription. For lncRNAs, multiple mechanisms are involved in the pathophysiology of depression: transcriptional activation: lncRNAs can activate the expression of target genes via (1) recruiting transcriptional factors to upstream open reading frames; (2) suppressing transcriptional factors to upstream open reading frames; (3) recruiting chromatin modifying factors to alter chromatin structure; (4) suppressing interacting proteins and RNP-complexes to target genes. For circRNAs, they are generated from back-splicing and canonical splicing of an mRNA transcript. These circRNAs are associated with homer scaffolding protein 1, regulate cell proliferation, and inhibit JAK2/STAT3 signal, leading to neuropathological changes related to depression. For miRNAs, multiple mechanisms, including mRNA degradation or inhibition by the RISC complex, activate depression. These mechanisms induce gene expression changes, which are associated with several molecular pathways of depression. RISC RNA-induced silencing complex, RNP ribonucleoprotein complexes, STAT3 signal transducer and activator of transcription 3, SERT serotonin transporter, BDNF brain-derived neurotrophic factor, GR glucocorticoid receptor, JAK2-STAT3 Janus kinase 2 and signal transducer and activator of transcription 3

Fig. 5

Functional mechanisms of representative miRNAs involved in depression. A variety of miRNAs can influence neurodevelopment, synaptic plasticity and neurotransmitters by regulating their target genes, thus leading to depression. PTEN phosphatase and tensin homolog deleted on chromosome ten, PI3K phosphoinositide 3-kinase, GRM metabotropic glutamate receptor, mEPSC/sEPSC miniature excitatory postsynaptic current/spontaneous excitatory postsynaptic current, SERT serotonin transporter, BDNF brain-derived neurotrophic factor

Fig. 6

Schematic diagram illustrating how the molecular basis of m⁶A and other reported RNA modifications relates to depression. The modification of m⁶A in MDD is regulated by the action of a complex network of proteins: “writers”, which include METTL3, METTL14, WTAP and RBM15–methylate RNA; “erasers”, which include ALKBH5 and FTO–demethylate RNA; and “readers”, which include eIF3, YTHDF1, IGF2BPs and HNRNPA2B1-recognize m⁶A. Other RNA modifications associated with MDD include N4-acetylcytidine (ac4C) and 5-methylcytosine (m5C). NAT10 can regulate mRNA translation efficiency by catalyzing ac4C while NSUN catalyzes m5C. The molecular consequences of these enzymes involve a variety of pathophysiological mechanisms related to MDD. METTL3 methyltransferase-like 3, METTL14 methyltransferase-like 14, WTAP Wilms tumor 1-associated protein, RBM15 RNA-binding motif protein 15, FTO obesity-associated protein, ALKBH5 Alkb homolog 5, eIF3 eukaryotic initiation factor 3, YTHDF1 YT521-B homology N6-Methyladenosine RNA Binding Protein 1, IGF2BPs insulin-like growth factor 2 mRNA binding proteins, CGC cerebellar granule cells, SIRT sirtuin, Adrb2 Adrenoceptor 2, CRY1/2 circadian regulator cryptochrome 1 and 2, FAAH fatty acid amide hydrolase, LRP2 lipoprotein receptor-related protein 2, Gab1s growth factor receptor-bound protein 2 associated binding protein 1

Fig. 7

Targeting epigenetic modifications by potential antidepressants and relevant behavioral changes observed in rodents. a Different HDAC inhibitors, including MS-275, sodium, and butyrate can block histone deacetylation and promote the expression of target genes. DNMT inhibitors, including cannabidiol, s-adenosyl methionine and quetiapine activate DNA demethylation patterns to promote the expression of target genes. b These epigenetic variations lead to important recovery in the neural circuits, synaptic plasticity, astrocyte morphological changes, etc. c Improved depression-like behaviors in rodents after implementing drugs interfering with epigenetic mechanisms