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A Wheel of Time: the Circadian Clock, Nuclear Receptors, and Physiology

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A Wheel of Time: the Circadian Clock, Nuclear Receptors, and Physiology Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE A wheel of time: the circadian clock, nuclear receptors, and physiology Xiaoyong Yang1 Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06519, USA It is a long-standing view that the circadian clock func- The rhythmic production and circulation of many tions to proactively align internal physiology with the hormones and metabolites within the endocrine system 24-h rotation of the earth. Recent studies, including one is instrumental in regulating regular physiological pro- by Schmutz and colleagues (pp. 345–357) in the February cesses such as reproduction, blood pressure, and metabo- 15, 2010, issue of Genes & Development, delineate strik- lism. Levels of circulating estrogen and progesterone ingly complex connections between molecular clocks and fluctuate with the menstrual cycle, which in turn affect nuclear receptor signaling pathways, implying the exis- circadian rhythms in women (Shechter and Boivin 2010). tence of a large-scale circadian regulatory network co- In parallel with a diurnal rhythm in circulating adrenocor- ordinating a diverse array of physiological processes to ticotropic hormone, secretion of glucocorticoids and aldo- maintain dynamic homeostasis. sterone from the adrenal gland rises before awakening (Weitzman 1976). Glucocorticoids boost energy produc- tion, and aldosterone increases blood pressure, together gearing up the body for the activity phase. Similarly, Light from the sun sustains life on earth. The 24-h plasma levels of thyroid-stimulating hormone and triiodo- rotation of the earth exposes a vast number of plants thyronine have a synchronous diurnal rhythm (Russell and animals to the light/dark cycle. Consequently, the et al. 2008). A broad range of metabolites—such as glucose, behavior and physiology of numerous living organisms free fatty acids, cholesterol, and bile acids—also exhibit exhibit circadian rhythms. The word ‘‘circadian’’ is de- diurnal fluctuation. A number of these hormones and rived from Latin circa diem, which means ‘‘about a day.’’ metabolites serve as ligands for nuclear receptors that Behavioral rhythms such as sleeping, food seeking, and direct a large array of transcriptional programs involved predator avoidance are thought to help animals survive. in lipid and carbohydrate metabolism (Chawla et al. 2001). Physiological rhythms such as body temperature, blood A survey of the diurnal expression profile of the mRNAs pressure, and metabolism also anticipate and adapt to encoding all 49 mouse nuclear receptors revealed that predictable changes in the environment to maintain the more than half of receptors follow rhythmic cycles in key overall well-being of animals (Young 2000). metabolic tissues (Yang et al. 2006). Together, these Circadian rhythms are controlled by evolutionarily observations suggest a complex interaction between the conserved internal clocks residing in most tissues of the circadian clock and nuclear receptor signaling (Yang et al. body. The central clock is located in the suprachiasmatic 2007; Teboul et al. 2008). Several recent studies lend nucleus (SCN) of the hypothalamus and is entrained further insight into an elaborate ‘‘wheel of time’’ composed directly by light (Hatings et al. 2008). This master of molecular clocks and nuclear receptors, which together pacemaker can synchronize circadian oscillators in pe- help shape an emerging perspective on ‘‘design principles’’ ripheral tissues, yet underlying neural and humoral and biological implications of the clock–receptor signaling mechanisms remain obscure. Besides light, other external network. cues such as feeding and ambient temperature are also powerful Zeitgebers (from German for time givers) for peripheral clocks (Damiola et al. 2000; Brown et al. 2002). Hub of time: nuclear receptors at the core How these time cues act in concert to entrain tissue- of molecular clocks specific oscillators and evoke diverse physiological re- Circadian clocks are self-sustained, robust, and tunable sponses is poorly understood. Nevertheless, these processes molecular oscillators. At the core of both the central and clearly involve the endocrine system. peripheral clocks are two interlocked transcriptional/ post-translational feedback loops (Ko and Takahashi [Keywords: Circadian oscillator; transcription; protein–protein in- 2006). In the negative feedback loop, BMAL1/CLOCK teraction] heterodimers activate the transcription of Period genes 1Correspondence. E-MAIL [email protected]; FAX (203) 785-7499. (Per1, Per2,andPer3)andCryptochrome genes (Cry1 and Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1920710. Cry2) by recognizing E-box cis elements in their promoters. GENES & DEVELOPMENT 24:741–747 Ó 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org 741 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Yang The PER/CRY complex in turn inhibits the transcription of adrenal transcriptome revealed that a number of genes their own genes by blocking BMAL1–CLOCK activity. The involved in steroid biosynthesis are expressed in a rhyth- second feedback loop involves the ROR (a, b,andg)and mic fashion (Oster et al. 2006). Disruption of the adrenal REV-ERB (a and b) proteins, members of a subfamily of clock by tissue-specific knockdown of BMAL1 abolishes nuclear receptors that recognize similar cis-regulatory circadian rhythms in steroidogenic gene expression and elements (ROREs) on target genes. RORs act as transcrip- glucocorticoid production (Son et al. 2008). Cry-null mice tional activators, and REV-ERBs are repressors. BMAL1/ showed a dramatic increase in aldosterone production CLOCK binds to E-box elements present in Ror and Rev- and resultant hypertension, which is due to the loss of erb genes and activate their transcription. RORs and REV- repression of Hsd3b6, a gene involved specifically in ERBs in turn drive rhythmic transcription of the Bmal1 steroidogenesis in the adrenal cortex (Doi et al. 2010). gene by alternately binding to ROREs in its promoter A range of ligands can be produced in local tissues. (Preitner et al. 2002; Liu et al. 2008). Heme is a porphyrin that functions as a prosthetic group Theoretically, a negative feedback loop with time delay for enzymes involved in oxygen and electron transport. is sufficient to generate an oscillator. Why does the Recently, two independent studies identified heme as an molecular clock adopt the ‘‘two-loop’’ design principle? endogenous ligand for REV-ERBa (Raghuram et al. 2007; Recent studies with synthetic oscillators in bacteria and Yin et al. 2007). Interestingly, the circadian clock and mammalian cells as well as computational modeling heme biosynthesis are reciprocally regulated (Kaasik and demonstrate that a second feedback loop would make an Lee 2004). Expression of ALAS1, the rate-limiting enzyme oscillator robust and tunable (Stricker et al. 2008; Tigges in heme biosynthesis, is under clock control, resulting in et al. 2009). In the clockwork, these features are likely to oscillation in the intracellular level of heme and its be accomplished by the ROR/REV-ERB/BMAL1 loop. association with REV-ERBa. Another example is that the circadian clock regulates cyclic expression of HMG- CoA reductase and cholesterol 7a-hydroxylase, the rate- The clock control of nuclear receptor pathways limiting enzymes in cholesterol and bile acid biosynthe- One of the major efforts in circadian biology is to define sis, respectively (Le Martelot et al. 2009). This is believed molecular pathways by which the core clockwork regu- to lead to cyclic production of oxysterols and bile acids, lates physiology and behavior. It has been demonstrated and activation of their corresponding receptors, LXR and that many nuclear receptors exhibit circadian-like pat- FXR. Therefore, cyclic production of ligands for nuclear terns of expression (Yang et al. 2006). Recent studies receptors provides a potential means of circadian regula- reveal a few of the nuclear receptor genes as being direct tion of metabolism. targets of the circadian clock. Peroxisome proliferator- activated receptor-a (PPARa) and PPARg regulate lipid The clock entrainment by nuclear receptors metabolism and energy homeostasis by coordinated ac- tions in a variety of tissues (Evans et al. 2004). Ppara Peripheral clocks appear to act as the integrators of transcription is induced by CLOCK and BMAL1 via an signals from the light-sensing central clock and other intronic E-box-rich region (Oishi et al. 2005; Canaple physiological cues. The nature of the signals that entrain et al. 2006). In contrast, PPARg expression is regulated by peripheral clocks in individual tissues remains obscure. two clock-controlled genes, albumin gene D-site-binding Serving as endocrine and metabolic sensors, a number of protein (Dbp) and E4 promoter A-binding protein 4 nuclear receptors have been implicated in clock entrain- (E4bp4). DBP is an activator, whereas E4BP4 is a repressor. ment (Yang et al. 2007; Kovac et al. 2009). Together, they induce oscillation of PPARg expression by Early studies showed that glucocorticoids are involved binding reciprocally to the D-boxes located in the first in the phase resetting of peripheral clocks in response to exon (Takahashi
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