Role of MSK in chromatin remodelling underlying stress-induced transcriptional induction in dentate gyrus granule neurons and behavioural adaptation

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

Abstract

Stress is part of everybody's every day 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 are taking 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 brain learns from stressful events. We have recently discovered that after stress certain molecular processes ('histone modifications') are taking place 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 the stressful event. These processes are triggered by certain hormones which are released within the brain or by hormone glands and that bind to receptors on the cell surface or inside these cells. The hormones do not trigger the molecular processes in the nucleus directly but do so via so-called signalling molecules. Our proposal aims to identify those signalling molecules and determine how these molecules act in order to gain insight into how nerve cells 'learn' from stressful events.

Technical Summary

Exposure to 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) 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)/MAPK/ERK signalling mechanisms. Moreover, signalling to the chromatin was disrupted by genetic deletion of the principal histone H3 kinase Mitogen- and Stress-activated Kinase (MSK). Of relevance, MSK is also a potent CREB kinase. We hypothesise that MSK is a key mediator of psychological stress-activated GR and NMDA/MAPK/ERK signalling to the chromatin that results in transcriptional activation and encoding of memory of the stressful event. In these processes, (1) GR and ERK concertedly activate MSK which then phosphorylates histone H3 (P-H3); (2) also, the activated MSK through phosphorylation of CREB and subsequent recruitment of histone acetyl transferase (HAT) activity indirectly drives the acetylation of P-H3 (PAc-H3); and (3) the PAc-H3-evoked chromatin remodelling results in activation of gene expression that is critical for the memory formation associated with the stressful event. To test this hypothesis we will use state-of-the-art inducible tissue-specific mutant mice and lentiviral-driven RNA interference technology in combination with neuroanatomical, immunohistochemical and behavioural analyses.

Publications

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

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Papadopoulos A (2011) GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus. in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

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Reul, Johannes M.H.M. (2011) Brain, Behavior and Epigenetics

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

 
Description In our studies investigating the role of the ERK MAPK pathway, GR- as well as CREB-mediated signalling in the phospho-acetylation of histone H3 and c-Fos induction in dentate gyrus granule neurons and the consolidation of the forced swimming-induced behavioural immobility response we have discovered the following:

-Forced swimming results in a transient phosphorylation (i.e. activation) of ERK1/2, MSK1 and Elk-1 in sparse dentate gyrus granule neurons.

-Immunofluorescence analyses show that GRs, pERK1/2, pMSK1, pElk-1, H3S10p-K14ac, c-Fos and Egr-1 co-localize in the same dentate neurons.

-Pharmacological and co-immuno-precipitation studies show that glucocorticoid hormones enhance the consolidation of the behavioural immobility response by enhancing the generation of pMSK1, pElk-1, H3S10p-K14ac, c-Fos and Egr-1 through a direct physical interaction of GR with pERK1/2. This is a novel, non-genomic mechanism of glucocorticoid hormone action enhancing ERK MAPK signalling to the chromatin and memory consolidation.
Exploitation Route Other scientists may take our findings forward to other behavioural models such as contextual fear conditioning and Morris water maze learning. Our work underscores the importance of histone H3 phosphorylation and acetylation for the control of gene transcription which may be important for other fields such as immune regulation and wound healing. Our work may also inspire other researchers to investigate the epigenetic and gene transcriptional consequences of signalling pathway activation in neurons and other cells in vivo and in vitro.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology