Glucocorticoid receptor suppresses gene expression of Rev‐erbα (Nr1d1) through interaction with the <scp>CLOCK</scp> complex

Murayama, Yuki; Yahagi, Naoya; Takeuchi, Yoshinori; Aita, Yuichi; Saber, Zahra Mehrazad; Wada, Nobuhiro; Li, EnXu; Piao, Xianying; Sawada, Yuko; Shikama, Akito; Masuda, Yukari; Nishi-Tatsumi, Makiko; Kubota, Midori; Izumida, Yoshihiko; Miyamoto, Takafumi; Sekiya, Motohiro; Matsuzaka, Takashi; Nakagawa, Yoshimi; Sugano, Yoko; Iwasaki, Hitoshi; Kobayashi, Kazuto; Yatoh, Shigeru; Suzuki, Hiroaki; Yagyu, Hiroaki; Kawakami, Yasushi; Shimano, Hitoshi

doi:10.1002/1873-3468.13328

Cited by 27 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nader et al showed that the transcription factor clock, a master regulator of circadian rhythm, acetylates GR and represses the transcriptional activity of several glucocorticoid-responsive genes [107]. GR also suppresses the expression of Rev-erbα (Nr1d1), which is also an important component of circadian regulation [108]. These findings provide new insights into the role of GR in the regulation of the circadian rhythm.…”

Section: The Role Of Gr In Physiological Conditionsmentioning

confidence: 99%

The Glucocorticoid Receptor in Cardiovascular Health and Disease

Liu

Zhang

Knight

et al. 2019

Cells

View full text Add to dashboard Cite

The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both animal models and humans has begun to unravel the profound complexity of glucocorticoid signaling and convincingly demonstrates that the glucocorticoid receptor has direct effects on the heart and vessels in vivo and in vitro. This research has contributed directly to improving therapeutic strategies in human disease. The glucocorticoid receptor is activated either by the endogenous steroid hormone cortisol or by exogenous glucocorticoids and acts within the cardiovascular system via both genomic and non-genomic pathways. Polymorphisms of the glucocorticoid receptor are also reported to influence the progress and prognosis of cardiovascular disease. In this review, we provide an update on glucocorticoid signaling and highlight the critical role of this signaling in both physiological and pathological conditions of the cardiovascular system. With increasing in-depth understanding of glucocorticoid signaling, the future is promising for the development of targeted glucocorticoid treatments and improved clinical outcomes.

show abstract

Section: The Role Of Gr In Physiological Conditionsmentioning

confidence: 99%

The Glucocorticoid Receptor in Cardiovascular Health and Disease

Liu

Zhang

Knight

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…Interestingly, glucocorticoidinduced phase-shifting did not occur in PER1 knockout models. This suggests that Per plays a major role in mediating the effects of glucocorticoids on other circadian components of the clock mechanism, such as Bmal1, Rev-Erb, and Clock (Koyanagi et al 2006), even though glucocorticoids can directly repress REV-ERB expression (Murayama et al 2019) and CLOCK and CRY have been shown to physically interact with the GR, inhibiting its transcriptional activity (Nader et al 2009, Lamia et al 2011 (Fig. 3).…”

Section: Is the Glucocorticoid Effector System The Watchmaker?mentioning

confidence: 99%

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

Minnetti

Hasenmajer

Pofi

et al. 2020

Journal of Endocrinology

View full text Add to dashboard Cite

The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing’s syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.

show abstract

“…Besides heterodimerization on DNA, GR has been suggested to form other protein-protein interactions on chromatin which tether GR to enhancers independently of its DBD. This includes interaction with COUP-TFII, STAT5, PPARα and the molecular clock components BMAL1, CLOCK, and REV-ERBα, influencing GR activity and hepatic metabolism ( 82 , 106 , 115 , 116 , 119 ). For example, COUP-TFII protein interaction with GR is important for GC-induced promoter activity and hepatic Pck1 gene expression ( 106 ).…”

Section: Gr Operates In Transcriptional Network To Control Hepatic Gmentioning

confidence: 99%

“…Also, GR is suggested to be recruited to a subset of sites via tethering to DNA-bound PPARα to regulate metabolic genes in the liver including Pdk4 ( 114 ). Moreover, GR tethering to the BMAL1-CLOCK complex is suggested to repress hepatic Rev-erb α expression ( 115 ), demonstrating how GR and the molecular circadian clock interconnect to regulate shared gene programs.…”

Section: Gr Operates In Transcriptional Network To Control Hepatic Gmentioning

confidence: 99%

“…Moreover, indirect interactions between GR and REV-ERBα have also been observed. REV-ERBα inhibits GR protein expression and nuclear localization ( 53 ), and GR inhibits REV-ERBα RNA expression ( 156 ) by forming a complex with CLOCK and BMAL1, where GR may be tethered to the regulatory site of the REV-ERBα gene ( 115 ).…”

Section: Examples Of Key Hepatic Gene Regulatory Network Controlled mentioning

confidence: 99%

See 1 more Smart Citation

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

2020

View full text Add to dashboard Cite

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.

show abstract

Glucocorticoid receptor suppresses gene expression of Rev‐erbα (Nr1d1) through interaction with the CLOCK complex

Cited by 27 publications

References 40 publications

The Glucocorticoid Receptor in Cardiovascular Health and Disease

The Glucocorticoid Receptor in Cardiovascular Health and Disease

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

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

Contact Info

Product

Resources

About