Social defeat stress induces genome-wide 5mC and 5hmC alterations in the mouse brain

Abstract

Stress is adverse experience that require constant adaptation to reduce the emotional and physiological burden, or “allostatic load”, of an individual. Despite their everyday occurrence, a subpopulation of individuals is more susceptible to stressors, while others remain resilient with unknown molecular signatures. In this study, we investigated the contribution of the DNA modifications, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), underlying the individual differences in stress susceptibility and resilience. Genome-wide 5mC and 5hmC profiles from 3- and 6-month adult male mice that underwent various durations of social defeat were generated. In 3-month animals, 5mC and 5hmC work in parallel and do not distinguish between stress-susceptible and resilient phenotypes, while in 6-month animals, 5mC and 5hmC show distinct enrichment patterns. Acute stress responses may epigenetically “prime” the animals to either increase or decrease their predisposition to depression susceptibility. In support of this, re-exposure studies reveal that the enduring effects of social defeat affect differential biological processes between susceptible and resilient animals. Finally, the stress-induced 5mC and 5hmC fluctuations across the acute-chronic-longitudinal time course demonstrate that the negative outcomes of chronic stress do not discriminate between susceptible and resilient animals. However, resilience is more associated with neuroprotective processes while susceptibility is linked to neurodegenerative processes. Furthermore, 5mC appears to be responsible for acute stress response, whereas 5hmC may function as a persistent and stable modification in response to stress. Our study broadens the scope of previous research offering a comprehensive analysis of the role of DNA modifications in stress-induced depression.

Transcriptome Dynamics in Mouse Amygdala under Acute and Chronic Stress Revealed by Thiol-labeled RNA Sequencing

“…We used this method to investigate the RNA dynamics of a key brain region involved in stress conditions, the amygdala, under acute and chronic restraint stress. We found partial overlap in genes detected by SLAM-seq and RNA-seq, and over half of the overlapped up-regulated genes under CS condition had been implicated in chronic stress by previous studies [52][53][54][61][62][63][64].…”

“…5c). Expression of six out of the 11 overlapped genes is affected by chronic stress (Esrrg, Gabarapl2, Cct8, Vamp1, Nrsn1, Cplx1) [47,[52][53][54]. These genes all show bigger fold changes and 9 out of 11 genes also show higher significance levels for SLAM-seq than for RNA-seq (Fig.…”

Epigenetic modifications of DNA and RNA in Alzheimer’s disease

“…Mouse models of chronic stress recapitulate depression-like behaviors and exhibit global 5mC and 5hmC cortical alterations. In two separate studies, differentially hydroxymethylated regions were enriched for gene ontology terms associated with neurogenesis and synaptic signaling ( Cheng et al, 2018 ; Kuehner et al, 2023 ). Notably, hypoxia-inducible factors (HIFs) Hif3 and Hif1α, known to play neuroprotective roles, were found to be associated with stress-induced methylation changes.…”

New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity

“…Epigenetics is one of the hypotheses that neurexins modulate synaptic plasticity [ 82 ]. Epigenetics refers to long-lasting changes in gene expression that are regulated by transcriptional, post-transcriptional, intra- or post-translational mechanisms (such as DNA methylation, histone modifications, and microRNA regulation) that do not involve DNA sequence alteration and are usually characterized by stability and longevity [ 84 ]. A summary of neurexins and epigenetics can be found in Fig.…”