Stress and the dynamic genome: Steroids, epigenetics, and the transposome

Hunter, Richard G.; Gagnidze, Khatuna; McEwen, Bruce S.; Pfaff, Donald W.

doi:10.1073/pnas.1411260111

Cited by 118 publications

(83 citation statements)

References 112 publications

(129 reference statements)

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“…This repression is lost with repeated stress, suggesting the possibility that those retrotransposon elements may impair genomic stability under conditions of chronic stress (Hunter et al, 2015).…”

Section: Epigenetics Stress and Mood-related Behaviors: Search For mentioning

confidence: 99%

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

McEwen

Nasca

Gray

2015

Neuropsychopharmacol

1,121

769

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The hippocampus provided the gateway into much of what we have learned about stress and brain structural and functional plasticity, and this initial focus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex. Starting with the discovery of adrenal steroid, and later, estrogen receptors in the hippocampal formation, and subsequent discovery of dendritic and spine synapse remodeling and neurogenesis in the dentate gyrus, mechanistic studies have revealed both genomic and rapid non-genomic actions of circulating steroid hormones in the brain. Many of these actions occur epigenetically and result in ever-changing patterns of gene expression, in which there are important sex differences that need further exploration. Moreover, glucocorticoid and estrogen actions occur synergistically with an increasing number of cellular mediators that help determine the qualitative nature of the response. The hippocampus has also been a gateway to understanding lasting epigenetic effects of early-life experiences. These findings in animal models have resulted in translation to the human brain and have helped change thinking about the nature of brain malfunction in psychiatric disorders and during aging, as well as the mechanisms of the effects of early-life adversity on the brain and the body.

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Section: Epigenetics Stress and Mood-related Behaviors: Search For mentioning

confidence: 99%

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

McEwen

Nasca

Gray

2015

Neuropsychopharmacol

1,121

769

View full text Add to dashboard Cite

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“…These differences in chromatin remodeling in rats exposed to acute versus chronic intermittent restraint may be related in part to habituation of the HPA axis to chronic intermittent restraint stress. In an extension of their work, Hunter et al (2015) considered the ways in which exposure to stress could produce persistent alterations in neural and endocrine responses and behavior. They suggested that expression of retrotransposons may play a critical role in stabilizing genomic activity in stress-sensitive brain regions such as the hippocampus…”

Section: Neural Adaptations To Stress: Role Of Transcriptional Changesmentioning

confidence: 99%

Learning about stress: neural, endocrine and behavioral adaptations

McCarty

2016

Stress

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In this review, nonassociative learning is advanced as an organizing principle to draw together findings from both sympathetic-adrenal medullary and hypothalamic-pituitary-adrenocortical (HPA) axis responses to chronic intermittent exposure to a variety of stressors. Studies of habituation, facilitation and sensitization of stress effector systems are reviewed and linked to an animal's prior experience with a given stressor, the intensity of the stressor and the appraisal by the animal of its ability to mobilize physiological systems to adapt to the stressor. Brain pathways that regulate physiological and behavioral responses to stress are discussed, especially in light of their regulation of nonassociative processes in chronic intermittent stress. These findings may have special relevance to various psychiatric diseases, including depression and post-traumatic stress disorder (PTSD).

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“…In recent years, numerous studies in both human MDD and in animal models of depression have identified changes in gene expression, along with related alterations in chromatin structure and function, that contribute to aberrant forms of transcriptional and behavioral plasticity associated with depressive-like phenotypes (4)(5)(6)(7)(8)(9). Although multiple studies have successfully linked alterations in histone posttranslational modifications (PTMs) or chromatinremodeling events to chronic stress susceptibility or resilience (e.g., using a model of chronic social defeat stress-CSDS-an etiologically valid rodent model of human depression), the precise histone regulatory phenomena involved in stress-mediated behavioral responses remain poorly understood.…”

mentioning

confidence: 99%

Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

Lepack

Bagot

Peña

et al. 2016

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

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Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type-and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc)-a key limbic brain reward regionin the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stressassociated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.H3.3 | nucleus accumbens | depression | chronic social defeat stress | histone dynamics M ajor depressive disorder (MDD) affects ∼17% of the population, making it the most prominent and debilitating psychiatric disease worldwide (1). Current antidepressants (ADs) can take weeks to months to produce an effective therapeutic response, with about one-third of patients remaining nonresponsive to existing treatment strategies. Although the prevalence of MDD and a lack of sufficient treatment options highlight the importance of identifying new drug targets, progress has been hindered by a general lack of understanding of the precise molecular mechanisms underlying this disorder.The nucleus accumbens (NAc), a critical component of the brain's limbic reward circuitry, has become increasingly implicated in depression, as well as in mechanisms of antidepressant action (2, 3). In recent years, numerous studies in both human MDD and in animal models of depression have identified changes in gene expression, along with related alterations in chromatin structure and function, that contribute to aberrant forms of transcriptional and behavioral plasticity associated with depressive-like phenotypes (4-9). Although multiple studies have successfully linked alterations in histone posttranslational modifications (PTMs) or chromatinremodeling events to chron...

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Stress and the dynamic genome: Steroids, epigenetics, and the transposome

Cited by 118 publications

References 112 publications

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

Learning about stress: neural, endocrine and behavioral adaptations

Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

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