Epigenetic Mechanisms of the Glucocorticoid Receptor

Bartlett, Andrew A.; Lapp, Hannah E.; Hunter, Richard G.

doi:10.1016/j.tem.2019.07.003

Cited by 74 publications

(40 citation statements)

References 80 publications

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“…Upon GR binding to chromatin, the local nucleosome-sparse region expands and the accessibility of the chromatin is further increased trough recruitment of chromatin remodeling complexes such as SWI/SNF and additional TFs ( 86 – 88 ). In addition, GR facilitates recruitment of widely expressed coactivators including histone acetyl transferases CBP, P300, GRIP1, PCAF and SRC-2 and components of the Mediator complex such as MED1 and MED14 ( 56 , 66 , 73 , 89 , 90 ). Moreover, other important GR coactivators have been identified in the liver, including CRTC2 ( 91 ), SIRT1, PGC-1α ( 92 ), ASCOM complex ( 93 ) and SETDB2 ( 94 ).…”

Section: Genomic Actions Of Gr: General Conceptsmentioning

confidence: 99%

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

2020

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Glucocorticoids (GCs) and the glucocorticoid receptor (GR) are important regulators of development, inflammation, stress response and metabolism, demonstrated in various diseases including Addison's disease, Cushing's syndrome and by the many side effects of prolonged clinical administration of GCs. These conditions include severe metabolic challenges in key metabolic organs like the liver. In the liver, GR is known to regulate the transcription of key enzymes in glucose and lipid metabolism and contribute to the regulation of circadian-expressed genes. Insights to the modes of GR regulation and the underlying functional mechanisms are key for understanding diseases and for the development of improved clinical uses of GCs. The activity and function of GR is regulated at numerous levels including ligand availability, interaction with heat shock protein (HSP) complexes, expression of GR isoforms and posttranslational modifications. Moreover, recent genomics studies show functional interaction with multiple transcription factors (TF) and coregulators in complex transcriptional networks controlling cell type-specific gene expression by GCs. In this review we describe the different regulatory steps important for GR activity and discuss how different TF interaction partners of GR selectively control hepatic gene transcription and metabolism.

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Section: Genomic Actions Of Gr: General Conceptsmentioning

confidence: 99%

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

2020

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“…Most GRs interact with alreadyopen chromatin before receptor activation while de novo opening of the chromatin was reported at a minority of loci (Burd et al, 2012). Interactions between GR and local chromatin occur directly and indirectly through the recruitment of histone/DNA-modifying enzymes (Bartlett et al, 2019). At resting state, most "potential sites" for GR binding in the genome reside in the inaccessible chromatin.…”

Section: Epigenomic Primingmentioning

confidence: 99%

“…The DNA methylation is linked to changes of histone acetylation and phosphorylation that serve as a multi-layered code of epigenomic regulation used to update new information based on prior experience (Bousiges et al, 2013;Crosio et al, 2003). Such feed-forward mechanisms can operate in multiple environmental and behavioral contexts to regulate the precision and magnitude of responses to glucocorticoid receptors (Bartlett et al, 2019). For example, BDNF signaling promotes nitrosylation of HDAC2, which reduces its enzymatic activity and localization on the chromatin (Nott et al, 2008).…”

Section: Epigenomic Primingmentioning

confidence: 99%

Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks

Huzard

Rappeneau

Meijer

et al. 2020

Stress

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The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments.

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“…Stressful life events, especially those during childhood, are known to increase the risk for adult-onset ADs. 69 Stress is known to activate many neuronal circuits, like those in the hippocampus, 70 and the hypothalamicpituitary-adrenal (HPA) axis. Genes encoding proteins associated with the HPA axis like the glucocorticoid receptor (GR or NR3C1), corticotropin releasing factor (CRF), FK506 binding protein 5 (FKBP5; a co-chaperone of the glucocorticoid receptor), proopiomelanocortin (POMC), and vasopressin have been found to show abnormalities in DNA methylation by previous studies.…”

Section: Rat Hippocampusmentioning

confidence: 99%

<p>The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders</p>

Peedicayil¹

2020

NDT

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There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the pathogenesis of anxiety disorders (ADs). This article discusses the role of epigenetic mechanisms of gene expression in the pathogenesis of ADs. It also discusses the data so far obtained from preclinical and clinical trials on the use of epigenetic drugs for treating ADs. Most drug trials investigating the use of epigenetic drugs for treating ADs have used histone deacetylase inhibitors (HDACi). HDACi are showing favorable results in both preclinical and clinical drug trials for treating ADs. However, at present the mode of action of HDACi in ADs is not clear. More work needs to be done to elucidate how epigenetic dysregulation contributes to the pathogenesis of ADs. More work also needs to be done on the mode of action of HDACi in alleviating the signs and symptoms of ADs.

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Epigenetic Mechanisms of the Glucocorticoid Receptor

Cited by 74 publications

References 80 publications

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks

<p>The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders</p>

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