Abstract
Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.
Highlights
Major depressive disorder is a chronic, debilitating mental illness that is rising globally and its predominant cause appears to be chronic or persistent stress [1,2,3]
Alteration in brain-derived neurotrophic factor (Bdnf) gene function has been reported to be a major underlying cause where H3K9me2/3 and H3K27me2/3 appeared to play a critical role resulting in compromised hippocampal function and dentate gyrus (DG) neurogenesis. Considering these previous studies, which delineate the importance of repressive H3K9 and H3K27 methylation marks in mediating the effects of stress on various brain regions and the dearth of studies on histone demethylases, we focused on a family of lysine demethylases which act on H3K9me2/3
The present study aims to uncover the role of the KDM4 family, known as the Jumonji domain-containing histone lysine demethylase 2 (JMJD2) family, in DG neurogenesis in a mouse depression model of chronic social defeat stress (CSDS)
Summary
Major depressive disorder is a chronic, debilitating mental illness that is rising globally and its predominant cause appears to be chronic or persistent stress [1,2,3]. Evidence for adult neurogenesis even in old age has been found in rodents, nonhuman primates, and recently, in humans too [11,12] Factors such as stress, anxiety, depression, addiction, etc. Stress leads to the dysregulation of several genes through modifications in the epigenetic or chromatin remodelling events in and around their regulatory regions [21,25,26] Therapeutics such as antidepressants and electroconvulsive therapy (ECT) appear to act by altering neural epigenetic mechanisms [27,28] in the restoration of the affected hippocampal neurogenesis or its enhancement [29,30]
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