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Systems Biology of Mammalian Circadian Clocks ANRV404-PH72-28 ARI 18 January 2010 10:16 Systems Biology of Mammalian Circadian Clocks Hideki Ukai1 and Hiroki R. Ueda1,2 1Laboratory for Systems Biology and 2Functional Genomics Unit, RIKEN Center for Developmental Biology, Hyogo 650-0047, Japan; email: [email protected] Annu. Rev. Physiol. 2010. 72:579–603 Key Words First published online as a Review in Advance on transcriptional circuit, temperature compensation, singularity, November 13, 2009 artificial circuit The Annual Review of Physiology is online at by University of Tokyo on 02/14/10. For personal use only. physiol.annualreviews.org Abstract This article’s doi: Systems biology is a natural extension of molecular biology; it can be 10.1146/annurev-physiol-073109-130051 defined as biology after identification of key gene(s). Systems-biological Copyright c 2010 by Annual Reviews. research is a multistage process beginning with (a) the comprehensive Annu. Rev. Physiol. 2010.72:579-603. Downloaded from arjournals.annualreviews.org ! All rights reserved identification and (b) quantitative analysis of individual system com- 0066-4278/10/0315-0579$20.00 ponents and their networked interactions, which lead to the ability to (c) control existing systems toward the desired state and (d ) design new ones based on an understanding of the underlying structure and dynam- ical principles. In this review, we use the mammalian circadian clock as a model system and describe the application of systems-biological ap- proaches to fundamental problems in this model. This application has allowed the identification of transcriptional/posttranscriptional circuits, the discovery of a temperature-insensitive period-determining process, and the discovery of desynchronization of individual clock cells under- lying the singularity behavior of mammalian clocks. 579 ANRV404-PH72-28 ARI 18 January 2010 10:16 INTRODUCTION: SYSTEMS are approached as complex and dynamic BIOLOGY AS BIOLOGY AFTER systems. Systems biology is a natural extension IDENTIFICATION of molecular biology and can be defined as biology after identification of key gene(s). Recent large-scale efforts in genome se- We consider systems-biological research as quencing, expression profiling, and functional a multistage process (Figure 1) that comprises screening have produced an embarrassment four steps: ( ) identification of the whole net- of riches for life science researchers, and bio- a work structure through functional genomics logical data can now be accessed in quantities and comparative genomics (system identifica- that are orders of magnitude greater than were tion), ( ) prediction and validation of the sys- available even a few years ago. The growing b tem’s behavior to derive the design principle need for interpretation of data sets, as well as through the accurate measurement and (static) the accelerating demand for their integration to perturbation of network dynamics (system anal- a higher-level understanding of life, has set the ysis), ( ) control and repair of the network state stage for the advent of systems biology (1, 2), c toward the desired state through the precise and in which biological processes and phenomena abSystem identi!cation System analysis Divide into components Accurately measure E4BP4 DBP E4BP4 DBP TEF TEF HLF HLF BMAL2 BMAL2 BMAL1 BMAL1 0 CLOCK CLOCK Step A 24(0) Prediction Step B 23 1 NPAS2 NPAS2 22 2 6 h 21 3 Veri"cation 4 h Identify E/E'box D-box E/E'box D-box 20 4 CRY2 CRY2 FBXL3 FBXL3 19 5 CRY1 CRY1 18 6 RevErbAa RevErbAa 18 6 DEC1 DEC1 Oscillator 17 7 RevErbAb RevErbAb Step E DEC2 DEC2 16 8 RORa RORa 4 h Step C 15 9 GSK3b PER1 GSK3b PER1 RORb RORb 4 h 14 10 CKId CKId 13 11 PER2 PER2 12 PP1 RORc PP1 RORc CKIe PER3 RRE CKIe PER3 RRE Step D 12 PP2A PP2A 6 h Mammalian circadian Genetic network Genetic network Natural clock of clock of clock circadian rhythm Systems biology System control System design cdOperate intentionally Synthesize from scratch by University of Tokyo on 02/14/10. For personal use only. Design Stimuli Reconstruction 1 E4BP4 DBP TEF E/E'-box D-box RRE HLF 0.75 BMAL2 BMAL1 Control 0.5 Rev CLOCK CRY1 PER1 CLOCK E4BP4 DBP NPAS2 Annu. Rev. Physiol. 2010.72:579-603. Downloaded from arjournals.annualreviews.org RORa E/E'box D-box Repair 0.25 ErbAa CRY2 FBXL3 CRY1 RevErbAa Rev DEC1 RevErbAb 25 50 75 100 125 150 175 CRY2 PER2 BMAL1 TEF RORb DEC2 RORa ErbAb GSK3b PER1 RORb CKId PER2 −0.25 RORc PP1 CKIe PER3 RRE −0.5 Time (h) DEC1 PER3 NPAS2 HLF RORc PP2A −0.75 DEC2 BMAL2 Natural Operated Network Genetic network circadian rhythm circadian rhythm components of clock Figure 1 Systems biology. (a) Systems-biological research begins with comprehensive identification. In this step, individual system components and their networked interactions are comprehensively identified. (b) In the second step, to derive the design principle of a target system, the behavior of the system is predicted and validated through an accurate measurement with perturbations. (c) An understanding of the design principle of the system is needed to derive the method of controlling the system toward the desired state. (d ) Finally, the level of understanding is confirmed by reconstruction of the system. 580 Ukai Ueda · ANRV404-PH72-28 ARI 18 January 2010 10:16 dynamic perturbation of its components (sys- IDENTIFICATION OF CLOCKS tem control), and ( ) reconstruction and design d Following the completion of genome projects of systems based on the design principles de- for species such as mouse and human, Temperature rived from the identified structure and observed genome-wide resources such as small interfer- compensation: dynamics (system design). These processes are ing RNA (siRNA) and complementary DNA phenomenon that required to elucidate the design principles of causes the period of an (cDNA) libraries have undergone considerable complex and dynamic biological systems, such oscillation to be stable expansion. Development of high-throughput as the mammalian circadian clock. despite temperature technologies also allows efficient use of these change resources. These genome-wide resources and SCN: suprachiasmatic MAMMALIAN CIRCADIAN technologies, as well as genome-associated in- nucleus CLOCK AS A MODEL SYSTEM formation, allow us to comprehensively identify complex systems such as the mammalian circa- The mammalian circadian clock is an ideal dian clock (system identification). model system for the study of complex and dy- namic biological systems. The mammalian cir- cadian clock consists of complexly integrated Identification of the feedback and feed-forward loops (3) and ex- Transcriptional Circuit hibits well-defined dynamical properties (4), The mammalian circadian master clock is pri- including (a) endogenous oscillations with an marily located in the suprachiasmatic nucleus approximately 24-h period, (b) entrainment to (SCN) (3). Transcript analyses have indicated external environmental changes (temperature that circadian clocks are not restricted to SCN and light cycle), (c) temperature compensation but are found in various tissues (6), including over a wide range of temperatures, and (d ) syn- liver, and in cultured fibroblast cells such as Rat- chronization of multiple cellular clocks despite 1 (7, 8), NIH3T3 (9), and U2OS (10) cells. In- the inevitable molecular noise. All of these dy- creasing numbers of so-called clock genes were namical properties would be difficult to elu- identified in mammalian clocks; these genes in- cidate without utilizing such system-level ap- clude three basic helix-loop-helix (bHLH)-PAS proaches. In addition to its advantages as a (PER-ARNT-SIM)transcription factors (Clock, basic model system for systems-biological re- Npas2, and Arntl; the latter is also known as search, the circadian clock is intimately in- Bmal1 or Mop3) (11–14), two period genes (Per1 volved in the control of metabolic and physi- and Per2) (15, 16), two cryptochrome genes ological processes (3, 5), and its dysregulation (Cry1 and Cry2) (17, 18), casein kinase I epsilon by University of Tokyo on 02/14/10. For personal use only. is associated with the onset and development of and delta (Csnk1e and Csnk1d ) (19, 20), and numerous human diseases, including sleep dis- two orphan nuclear hormone receptors (Nr1d1 orders, depression, and dementia. An improved and Rora, also known as RevErbα and Rorα, Annu. Rev. Physiol. 2010.72:579-603. Downloaded from arjournals.annualreviews.org system-level understanding promises to pro- respectively) (21, 22). A number of other tran- vide biomedical and clinical investigators with a scriptional factors also thought to function in powerful new arsenal with which to attack these the circadian regulation of gene expression were conditions. gradually clarified; these include four bZip- Some systems-biological efforts to elucidate family genes (Dbp, Tef,Hfl, and Nfl3; the latter is the design principles of complex and dynamic also termed E4bp4 ) (23, 24), three bHLH tran- biological systems such as the mammalian circa- scription factors (Arntl2, Bhlhb2, and Bhlhb3, dian clock have been reported. In the following also known as Bmal2, Dec1 or Stra13, and Dec2, sections, we describe in detail the strategies and respectively) (25), one period-related gene technologies developed for systems-biological (Per3) (26), and three genes related to Nr1d1 research, in addition to their applicability to and Rora (Nr1d2, Rorb, and Rorc, also known the specific case of the mammalian circadian as RevErbβ, Rorβ, and Rorγ , respectively) clock. (22, 27). www.annualreviews.org Systems Biology of Mammalian Clocks 581 • ANRV404-PH72-28 ARI 18 January 2010 10:16 Molecular interactions among these clock Three types of clock-controlled elements genes and clock-related genes have also been (CCEs)—E-boxes (5!-CACGTG-3!) (57) at least partly identified. For example, the plus E!-boxes (5!-CACGTT-3!) (58, 59), CCEs: clock- controlled elements transcription factors CLOCK and BMAL1 D-boxes [5!-TTATG(C/T)AA-3!] (60), and dimerize and directly and indirectly activate RevErbA/ROR-binding elements (RREs) [5!- dLuc: destabilized luciferase transcription of the Per and Cry genes through (A/T)A(A/T)NT(A/G)GGTCA-3!] (61)—are E-box elements (5!-CACGTG-3!) (28, 29).
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