The Molecular Basis of Depression: Implications of Sex-Related Differences in Epigenetic Regulation

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide. Although the etiology and pathophysiology of MDD remain poorly understood, aberrant neuroplasticity mediated by the epigenetic dysregulation of gene expression within the brain, which may occur due to genetic and environmental factors, may increase the risk of this disorder. Evidence has also been reported for sex-related differences in the pathophysiology of MDD, with female patients showing a greater severity of symptoms, higher degree of functional impairment, and more atypical depressive symptoms. Males and females also differ in their responsiveness to antidepressants. These clinical findings suggest that sex-dependent molecular and neural mechanisms may underlie the development of depression and the actions of antidepressant medications. This review discusses recent advances regarding the role of epigenetics in stress and depression. The first section presents a brief introduction of the basic mechanisms of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs. The second section reviews their contributions to neural plasticity, the risk of depression, and resilience against depression, with a particular focus on epigenetic modulators that have causal relationships with stress and depression in both clinical and animal studies. The third section highlights studies exploring sex-dependent epigenetic alterations associated with susceptibility to stress and depression. Finally, we discuss future directions to understand the etiology and pathophysiology of MDD, which would contribute to optimized and personalized therapy.

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

“…Animal and human studies have shown that epigenetic mechanisms can regulate DNA transcription in response to environmental factors and may play a role in the pathological and physiological processes of depression [ 13 ]. Epigenetics refers to changes in expression level of a gene not involving changes in the DNA sequence, such as DNA methylation, histone modification, noncoding RNA, and chromatin remodeling [ 14 ]. DNA methylation means modification of the cytosine rings in a CpG dinucleotide using covalent binding of a methyl group of carbon 5 of cytosine of CpG dinucleotide in the genome by DNA methyltransferase.…”

Long Noncoding RNA LINC00473 Ameliorates Depression-Like Behaviors in Female Mice by Acting as a Molecular Sponge to Regulate miR-497-5p/BDNF Axis

“…Further analysis targeting the gender difference demonstrated that the differential lncRNA expression was more significant in female patients than that in males. A research reported that the expression of LINC00473 was downregulated in depressed patients [ 9 ]. More interestingly, another study revealed that LINC00473 was decreased in depressed females only [ 10 ].…”

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex

“…We used only male mice; therefore, our results are not necessarily generalizable to female mice. Given that previous evidence suggests sex-specific transcriptome changes in MDD and differences in antidepressant responsiveness between genders ( 62 , 63 , 64 ), further studies are necessary. Nonetheless, our study provides important information for subsequent studies aimed at exploring both male and female antidepressant responders.…”