KAP1-Mediated Epigenetic Repression in the Forebrain Modulates Behavioral Vulnerability to Stress

Jakobsson, Johan; Cordero, M. Isabel; Bisaz, Reto; Groner, Anna C.; Busskamp, Volker; Bensadoun, Jean-Charles; Cammas, Florence; Losson, Régine; Mansuy, Isabelle M.; Sandi, Carmen; Trono, Didier

doi:10.1016/j.neuron.2008.09.036

Cited by 109 publications

(90 citation statements)

References 65 publications

(79 reference statements)

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“…Of interest is the observation that mice bearing a forebrain deletion of KAP-1 show increased anxiety and deficits in hippocampus-dependent memory (26). Those data, taken together with our present findings showing remarkable hippocampal specificity, suggest that dysregulation of heterochromatinmediated transposon silencing may have an impact on spatial memory, anxiety, and hippocampal function.…”

Section: Discussionsupporting

confidence: 71%

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Hunter

Murakami

Dewell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute (30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements.heterochromatin | ncRNA | posttraumatic stress disorder | transposon

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Section: Discussionsupporting

confidence: 71%

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Hunter

Murakami

Dewell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

View full text Add to dashboard Cite

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“…However, in some cases, the H3K9 mark can be associated with increased transcription when it is found in the coding region rather than the promoter region of a gene (50). The change in H3K9me3 levels admits other potential explanations, given the role of this mark in heterochromatin formation (51,52); it seems possible that the increase in this mark represents stress-induced facultative heterochromatin formation, perhaps via the KAP-1 pathway, which is present in the mammalian hippocampus and seems to play a role in the transcriptional response to stress in that region (53).…”

Section: Discussionmentioning

confidence: 99%

Regulation of hippocampal H3 histone methylation by acute and chronic stress

Hunter

McCarthy²,

Milne³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

261

190

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The hippocampal formation is a brain region noted for its plasticity in response to stressful events and adrenal steroid hormones. Recent work has shown that chromatin remodeling in various brain regions, including the hippocampus, is associated with the effects of stress in a variety of models. We chose to examine the effects of stress, stress duration, corticosterone administration, and fluoxetine treatment on the levels of hippocampal histone H3 methylation at lysines 4, 9, and 27, marks associated, respectively, with active transcription, heterochromatin formation, and transcriptional repression. We found that acute stress increased the levels of H3K9 tri-methylation (H3K9me3) in the dentate gyrus (DG) and CA1, while it reduced levels of H3K9 mono-methylation (H3K9me1) and H3K27 tri-methylation (H3K27me3) in the same regions, and had no effect on levels of H3K4 tri-methylation (H3K4me3). Seven days of restraint stress reduced levels of H3K4me3 in the CA1 and H3K27me3 in the DG and CA1, while increasing basal levels of H3K9me3. Chronic restraint stress (CRS) for 21 days mildly increased levels of H3K4me3 and reduced H3K9me3 levels in the DG. Treatment with fluoxetine during CRS reversed the decrease in DG H3K9me3, but had no effect on the other marks. These results show a complex, surprisingly rapid, and regionally specific pattern of chromatin remodeling within hippocampus produced by stress and anti-depressant treatment that may open an avenue of understanding the interplay of stress and hippocampal gene expression, and reveal the outlines of a potential chromatin stress response that may be diminished or degraded by chronic stress.brain ͉ chromatin ͉ corticosteroids ͉ fluoxetine

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“…A detailed description of the maze and standard training conditions has been published earlier. 23 Briefly, training was conducted over 3 days (four trials per day with a inter-trial interval of 15 min). The latency to find the platform was measured as an index of the learning and memory abilities of the animals, as no differences in swim speed were found between the two genotypes.…”

Section: Preparation Of Hippocampal Tissue and Western Blot Analyses mentioning

confidence: 99%

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

et al. 2010

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Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety-and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

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KAP1-Mediated Epigenetic Repression in the Forebrain Modulates Behavioral Vulnerability to Stress

Cited by 109 publications

References 65 publications

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response

Regulation of hippocampal H3 histone methylation by acute and chronic stress

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

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