The role of epigenetic processes in mediating the molecular and behavioural responses to stress in the dentate gyrus

Lead Research Organisation: University of Bristol
Department Name: Henry Wellcome LINE


Stress is part of everybody's daily life. We need to respond appropriately to stressful events and normally we learn from them to cope better the next time they are imposed on us. These learning and adaptation processes take place in the brain. These processes must work properly as improper functioning can cause illness such as depression and anxiety. However, we currently do not fully know how the healthy brain learns from stressful events. We have recently discovered that after stress certain molecular processes ('epigenetic modifications') occur in the nucleus of nerve cells which we think are crucial for the expression of certain genes necessary for the adaptation of these cells to a stressful event. Our proposal aims to identify those epigenetic modifications and the genes affected by these modifications. Collection of this information is crucial in order to gain insight into how nerve cells 'learn' from stressful events. Insight into these processes and the function of the genes involved will help to develop new drugs for the treatment of major depression and anxiety disorders that currently burden many people in our society.

Technical Summary

Dealing with a psychologically stressful event requires, in addition to generation of the acute stress response, cognitive processing in order to learn from it and thus to be able to respond more appropriately in case of future recurrences. Insight into the molecular and cellular mechanisms underlying stress coping and stress processing in the brain is clearly vital for the development of strategies to improve the quality of life of humans and animals. We have found that, in the case of a learned behavioural response to stress in rats and mice, this process involves chromatin remodelling (driven by phosphorylation and subsequent acetylation of histone H3 (H3S10p-K14ac)) to induce transcriptional activation in dentate gyrus neurons in the limbic brain which is mediated through concurrent stimulation of glucocorticoid receptor (GR) and NMDA receptor (NMDA-R)/ERK/MSK signalling mechanisms. We hypothesise that in dentate neurons (1) the psychological stress-activated H3S10p-K14ac epigenetic marks are located in a specific set of gene promotors; (2) establishment of these marks is associated with site-specific lysine methylation and/or de-methylation within H3 tails and de-methylation of DNA of the involved gene promotors; and (3) this complex of epigenetic modifications is required for activation of gene transcription that is critical for the memory formation associated with the stressful event; To test these hypotheses we will use state-of-the-art lentiviral-driven RNA interference technology, chromatin immuno-precipitation (ChIP), gene promoter identification using gene tiling microarrays (ChIP-chip), and methylomic profiling using microarrays in combination with neuroanatomical, immunohistochemical and behavioural analyses.


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Mifsud KR (2011) Epigenetic mechanisms in stress and adaptation. in Brain, behavior, and immunity

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Gutièrrez-Mecinas M (2011) Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2-MSK1-Elk-1 signaling. in Proceedings of the National Academy of Sciences of the United States of America

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Trollope AF (2012) Stress, epigenetic control of gene expression and memory formation. in Experimental neurology

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Reul JM (2015) Glucocorticoids, epigenetic control and stress resilience. in Neurobiology of stress

Description -The transcription-activating histone marks H3S10p-K14ac, H3 acetylation (H3K9ac, H3K14ac), H3K4me3 and overall H4 acetylation were enriched at the c-Fos promoter in dentate gyrus neurons under baseline conditions. Forced swimming increased H3S10p-K14ac enrichment; other marks remained unchanged. All marks, except H3S10p-K14ac, were also found at the neocortex c-Fos promoter. The suppressive marks H3K9me3 and H3K27me3 were not found at the c-Fos promoter. ChIP- Sequencing revealed that H3S10p-K14ac, H3K9ac and H3K4me3 are enriched at many hundreds of gene promoters of which many are involved in neuronal plasticity processes. Bioinformatics analysis of these exciting data is in progress.
-Histone H3 methylation (i.e. overall hippocampus H3K4me3, H3K9me3 and H3K27me3 levels (Western analysis), and these histone H3 methylation marks associated with the c-Fos and Egr-1 promoters in dentate neurons (ChIP)) did not change after forced swimming. Therefore, these histone marks do not seem to be involved in the forced swimming-induced behavioural immobility response.
-Forced swimming evoked a rapid DNA de-methylation of the c-Fos and Egr-1 gene promoters specifically in dentate neurons. Administration of the methyl donor S- adenosyl-methionine blocked the forced swimming-induced DNA de-methylation of the c-Fos and Egr-1 gene promoters, c-Fos and Egr-1 (protein) induction in dentate neurons and the behavioural immobility response but had no effect on the forced swimming-induced H3S10p-K14ac formation. Thus, induction of c-Fos and Egr-1 in dentate neurons requires both DNA de-methylation and H3S10p-K14ac formation; these appear to be independent epigenetic pathways. This dual epigenetic mechanism is not required for c-Fos and Egr-1 induction in the neocortex.
Exploitation Route Other researchers can apply our observations regarding the differential control of one transcription by distinct histone modifications in their models of gene transcriptional control of stress-related behaviour or other cellular, physiological or behavioural models.
Our findings will increase the awareness among other scientists that gene transcription is rapidly and powerfully regulated by the DNA methylation status of distinct CpGs within genes. Moreover, our finding that the concentration of S-adenosyl methionine is important in determining DNA methylation changes of genes after cellular stimulation is of great interest to other researchers studying DNA methylation in their systems in vivo and in vitro.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology