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Endocrine Functions of Brain Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The clock genes cycle in opposite phases and define the daily variations in physiological functions that shape the circadian rhythm. During the night, the PER‐CRY complex is degraded, and BMAL1:CLOCK can start a new cycle of transcription. The entire cycle takes about 24 h to complete. The BMAL1:CLOCK heterodimer also activates the transcription of other clock genes, such as reverse erythroblastosis virus (Rev-Erb) a and b, which repress Bmal1 gene expression. Several kinases and phosphatases that regulate the speed, precision, and functions of the circadian clock also contribute to circadian oscillations. Other important regulatory factors include ubiquitination, acetylation/deacetylation and methylation as well as input from microRNAs and several RNA-binding protein complexes.
Sleep deprivation therapy: A rapid-acting antidepressant
Published in S.R. Pandi-Perumal, Meera Narasimhan, Milton Kramer, Sleep and Psychosomatic Medicine, 2017
The results showed a significant and marked loss in rhythmicity in the top-ranked cyclic genes in MDD patients compared to controls and provided the first direct evidence of dysregulation in clock gene expression across six brain regions. The findings were independent of medication and cause of death. Dysregulated genes included the core circadian clock genes (i.e., BMAL1, PER1, PER2, PER3, Rev-Erbα, DBP, DEC1, and DEC2), which are essential to modulating virtually all rhythms throughout the body.84
Neurobiology of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
The SCN neurons house the circadian molecular hub, while the clock itself is composed of a series of transcriptional and translational feedback loops that result in the rhythmic expression of clock genes on a timescale of just over 24 hours. In the primary feedback loop, the transcription factors, Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1), heterodimerize and bind to E-box containing sequences in a number of genes including the three Period (PER) genes (PER1, PER2 and PER3) and two Cryptochrome (CRY) genes (CRY1 and CRY2). Over time PER and CRY proteins dimerize in the cytosol and are shuttled back into the nucleus where CRY proteins can directly inhibit the activity of CLOCK and BMAL1. In addition to this feedback loop, the CLOCK and BMAL1 proteins regulate the expression of Rev-erbα and ROR (retinoic acid-related orphan nuclear receptors) which in turn can repress or activate BMAL1 transcription respectively, through action at the Rev-Erb/ROR response element in the promoter. There are several key proteins which regulate the timing of the molecular clock through phosphorylation, sumoylation and other mechanisms. The enzymes, casein kinases, phosphorylate the PER, CRY and BMAL1 proteins altering their stability and nuclear entry; glycogen synthase kinase 3 beta (GSK3β) also phosphorylates the PER2 protein facilitating its nuclear entry.8 As alluded to above many controlling kinases, phosphatases and secondary feedback loops act on the molecular clock, contributing to great intricacy to the circadian apparatus. Significantly, circadian transcription factors are involved in the regulation and functioning of several other clock-controlled genes, which partake in a whole range of homeostatic actions in every body system. As will become clear in the ensuing sections, these sub-cellular mechanisms regulate the key physiological functions of the body in a circadian fashion.
Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma
Published in Chronobiology International, 2023
Lei Qian, Xiaochen Ding, Xiaoyan Fan, Shisen Li, Yihuan Qiao, Xiaoqun Zhang, Jipeng Li
The nuclear receptor 1D subfamily member NR1D1, which is also known as Rev-Erb, functions as a transcriptional repressor by binding specifically to the REV-ERB response element in its target genes (Harding and Lazar 1993). NR1D1 was shown to be intricately engaged in various cellular physiological processes, including cell differentiation, lipid metabolism, biosynthesis of mitochondria, and inflammatory reactions, among others (Raghuram et al. 2007; Yin et al. 2007). It was also reported that NR1D1 can be recruited to DNA damaged sites to inhibit repair, a process that is closely related to chemotherapy sensitivity in breast cancer (Kourtidis et al. 2010). Therefore, further studies on the biological function of NR1D1 will help uncover the pathogenesis of diseases induced by abnormal rhythms, which is of great importance to treating tumors.
Time-dependent effect of REV-ERBα agonist SR9009 on nonalcoholic steatohepatitis and gut microbiota in mice
Published in Chronobiology International, 2023
Yinhua Ni, Sujie Nan, Liujie Zheng, Liqian Zhang, Yufeng Zhao, Zhengwei Fu
REV-ERBs are typical nuclear receptors acting as master regulators of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis (Raza et al. 2022). A number of synthetic REV-ERB agonists have been developed for the treatment of relevant diseases regarding their role in positively influencing dysregulated metabolism and inflammation (Griffett et al. 2022). For example, REV-ERBα agonist SR9009 treatment reduces fat content and significantly improves dyslipidemia and hyperglycemia in diet-induced obese mice (Griffett et al. 2020). A recent study also found that the beneficial effects of REV-ERBα activation by SR9009 are associated with an overall improvement of hepatic health by suppressing hepatic fibrosis and inflammatory response in mice (Griffett et al. 2020). However, a broad range of the effect of REV-ERB activation in NASH mice remains exclusive. We have previously found that REV-ERBα directly regulates the tight junction protein, and the activation of REV-ERBα protects against the impaired gut barrier function, which might be partly related to the amelioration of NASH in mice (Ni et al. 2021). However, the time-dependent effect of REV-ERB activation on microbiota and the involvement of gut-liver interaction in SR9009-mediated alleviation of NASH remains unknown.
The nuclear receptor REV-ERBα regulates CYP2E1 expression and acetaminophen hepatotoxicity
Published in Xenobiotica, 2022
Li Zhang, Fugui Zhang, Yifei Xiao, Jianhao Du, Xingwang Zhang, Min Chen, Baojian Wu
REV-ERBα (also known as NR1D1) belongs to the superfamily of nuclear receptors and is a critical negative component of the circadian clock system (Yin et al. 2007; Yuan et al. 2019). It acts as a transcriptional repressor that represses gene transcription via binding to a Rev-erbα response element (RevRE) in the promoter region and subsequently recruiting the nuclear corepressor 1 (NCoR1) and histone deacetylase 3 (HDAC3) (Yin and Lazar 2005). REV-ERBα plays a significant role in regulation of various physiologic processes (e.g. lipid and glucose metabolism, adipogenesis, and inflammation), and thus is regarded as a promising therapeutic target for metabolic and inflammatory disorders (Fontaine and Staels 2007; Duez et al. 2008; Zhang et al. 2018; Zhou et al. 2020). In addition, Rev-erbα has been identified as an important regulator of drug-metabolising genes (Wang et al. 2020). For example, Rev-erbα ablation reduces glucuronidation of propofol by down-regulating UGT1A9 expression (Xu et al. 2020). Rev-erbα regulates the rhythmic expression of Ugt2b genes, thereby accounting for circadian variations in morphine metabolism (Zhang et al. 2019). However, it remains unclear whether and how REV-ERBα regulates CYP2E1 expression and activity.