Genomic and Epigenomic Responses to Chronic Stress Involve miRNA-Mediated Programming

Abstract

Stress represents a critical influence on motor system function and has been shown to impair movement performance. We hypothesized that stress-induced motor impairments are due to brain-specific changes in miRNA and protein-encoding gene expression. Here we show a causal link between stress-induced motor impairment and associated genetic and epigenetic responses in relevant central motor areas in a rat model. Exposure to two weeks of mild restraint stress altered the expression of 39 genes and nine miRNAs in the cerebellum. In line with persistent behavioural impairments, some changes in gene and miRNA expression were resistant to recovery from stress. Interestingly, stress up-regulated the expression of Adipoq and prolactin receptor mRNAs in the cerebellum. Stress also altered the expression of Prlr, miR-186, and miR-709 in hippocampus and prefrontal cortex. In addition, our findings demonstrate that miR-186 targets the gene Eps15. Furthermore, we found an age-dependent increase in EphrinB3 and GabaA4 receptors. These data show that even mild stress results in substantial genomic and epigenomic changes involving miRNA expression and associated gene targets in the motor system. These findings suggest a central role of miRNA-regulated gene expression in the stress response and in associated neurological function.

Analysis of Global Changes in Gene Expression Induced by Human Polynucleotide Phosphorylase (hPNPaseold‐35)

“…Thirty-one genes were identified with expression negatively correlating with c-myc and 29 with expression positively correlating with c-myc (Table S1). We further grouped the 60 c-myc correlating genes into biological categories using the functional annotation cluster analysis tool in DAVID [Huang et al, 2007; Babenko et al, 2012; Hanaoka et al, 2012], which resulted in the identification of 26 gene enrichment clusters with the highest enrichment score being 2.02. Some of the functional categories identified represented in Figure S6 were apoptosis, DNA repair, cytoskeleton and mRNA processing.…”

microRNA-124: a putative therapeutic target and biomarker for major depression

“…Recent evidence suggests that different types of stresses in rodents differentially regulate miRNAs in various brain areas [3][4][5]. Some of these miRNAs are either consistently up or downregulated during acute and chronic stress and some show longer-term adaptation to chronic stress [4,5].…”

“…Some of these miRNAs are either consistently up or downregulated during acute and chronic stress and some show longer-term adaptation to chronic stress [4,5]. Interestingly, acute restraint stress causes rapid changes in miRNA expression in a brain-region-specific manner that leads to altered synaptic efficacy mediated by mRNA translation localized at the synapse [4].…”

Epigenetic programming of the neuroendocrine stress response by adult life stress

“…Lastly, HDAC2 was found to be downregulated by 10-day social defeat stress in the NAc of defeated vs control mice, coinciding with increased accumbal H3K14 acetylation in the NAc (Covington et al 2009) and in the PVN of social avoidant vulnerable compared to resilient mice (Elliott et al 2010) R19 Review b c j dirven and others Epigenetics of stress response in adulthood (Table 2 for an overview of all reported region-specific stress-induced epigenetic changes). Rodent models have also demonstrated altered region-specific miRNA levels in response to both acute (Rinaldi et al 2010, Mannironi et al 2013, Hosoya et al 2016) and chronic stressors (Meerson et al 2010, Babenko et al 2012). …”