Molecular architecture of the mammalian circadian clock

doi:10.1016/j.tcb.2013.07.002

Trends in Cell Biology

Volume 24, Issue 2, February 2014, Pages 90-99

https://doi.org/10.1016/j.tcb.2013.07.002 Get rights and content

Highlights

•
The circadian clock generates molecular rhythms with 24 h periodicity.
•
Circadian control of physiology is distributed to peripheral tissues.
•
24 h timing arises from the ordered recruitment of clock proteins to promoters.
•
Many mechanisms are used to generate rhythmic output from the core molecular clock.
•
Clocks integrate with systemic cues to give flexibility to circadian physiology.

Circadian clocks coordinate physiology and behavior with the 24 h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24 h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease.

Section snippets

A clockwork physiology

Mammalian physiology and behavior are coordinated by an intrinsic molecular clock into rhythms that are synchronized with the 24 h solar day. Circadian (Latin circa diem, meaning ‘about a day’) synchronization allows anticipation of regular environmental changes to influence molecular and behavioral decisions that impact fitness and survival, including food intake and metabolism, predator/prey interactions, and the evasion of DNA damage from environmental insults, amongst others [1]. Circadian

A hierarchical timing system

Circadian rhythms are genetically encoded by a molecular clock located in nearly every cell that generates internal timing of approximately 24 h in the absence of external cues (Box 1). Molecular clocks located throughout the body in peripheral tissues are organized into a coherent, hierarchical system by a ‘master’ clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus [4]. The SCN is comprised of approximately 20 000 neurons that form a highly unified circadian network [5].

Peripheral clocks regulate tissue-specific expression patterns

Early microarray studies revealed that peripheral clocks regulate vast transcriptional programs to induce a single peak of expression once per day for each of the clock-controlled genes, representing approximately 10% of all expressed genes. These oscillating messenger RNA transcripts are specifically coordinated with tissue function, resulting in only ∼1–3% convergence in oscillating transcripts between liver, heart, muscle, and the SCN 28, 29, 30. Comparing clock-driven transcripts in the

Insight into the molecular clock mechanism

The heterodimeric CLOCK:BMAL1 complex is the essential positive regulator of circadian transcription in mammals, binding to several thousand sites throughout the genome in the liver with peak occupancy midday at circadian time (CT) CT5–8 (approximately 11 am to 2 pm) 39, 42. CLOCK:BMAL1 binding occurs primarily at consensus E-box DNA motifs and recruits complexes of the integral clock protein transcriptional repressors PER1, PER2, CRY1, and CRY2, with peak occupancy in the evening at CT15–18 [39]

Post-transcriptional/translational control of circadian output

Generation of the 24 h molecular clock that drives circadian changes in physiology and behavior is rooted in transcriptional regulation of integral clock genes, although it is surprisingly resilient to a reduction in overall transcriptional rates [92]. Outside these integral clock genes, post-transcriptional/translational regulation likely helps to provide additional flexibility by generating rhythms in mRNA transcripts or proteins in a tissue- or stimulus-dependent manner. For example, genes

Concluding remarks

Our lives are intimately tied to the external environment through the interaction of our intrinsic molecular clocks with the solar cycle. Knowledge of how internal clocks drive 24 h timing to temporally coordinate physiology has improved in recent years, but we still lack fundamental insight into the molecular basis of circadian timing and tissue-dependent control of physiology. Although built upon transcription-based feedback loops, it now appears that the majority of clock-controlled processes

Acknowledgments

We would like to thank the anonymous reviewers for their insightful comments and helpful suggestions. This work was supported by the National Institutes of Health (NIH P50 MH074924 and R01 MH078024 to J.S.T. and NIH P50 MH074924, R01 GM090247 and R21 NS079986 to C.B.G.) and by start-up funds from the University of California Santa Cruz (C.L.P.). J.S.T. is an Investigator in the Howard Hughes Medical Institute.

Glossary

Circadian time (CT): a standard of time based on the internal free-running period of a circadian clock. By convention, the onset of activity in diurnal organisms defines circadian time zero (CT 0; usually 6 am), whereas the onset of activity in nocturnal organisms defines circadian time 12 (CT 12).
Entrainment: synchronization of an internal circadian oscillator to an environmental stimulus that occurs at regular intervals (usually with ∼24 h periodicity).
Free-running: the state of a self-sustaining

References (115)

J. Mohawk et al.
Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators
Trends Neurosci.
(2011)
A. Liu
Intercellular coupling confers robustness against mutations in the SCN circadian clock network
Cell
(2007)
S. Brown
Rhythms of mammalian body temperature can sustain peripheral circadian clocks
Curr. Biol.
(2002)
K. Bae
Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock
Neuron
(2001)
Y. Lee
Stoichiometric relationship among clock proteins determines robustness of circadian rhythms
J. Biol. Chem.
(2011)
K-F. Storch
Intrinsic circadian clock of the mammalian retina: importance for retinal processing of visual information
Cell
(2007)
S. Panda
Coordinated transcription of key pathways in the mouse by the circadian clock
Cell
(2002)
F. Gachon
The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification
Cell Metab.
(2006)
N. Preitner
The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator
Cell
(2002)
A. Reddy
Circadian orchestration of the hepatic proteome
Curr. Biol.
(2006)

C. Vollmers

Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome

Cell Metab.

(2012)

S. Brown

(Re)inventing the circadian feedback loop

Dev. Cell

(2012)

R. Chen

Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism

Mol. Cell

(2009)

M. Ukai-Tadenuma

Delay in feedback repression by cryptochrome 1 is required for circadian clock function

Cell

(2011)

S. Khan

Identification of a novel cryptochrome differentiating domain required for feedback repression in circadian clock function

J. Biol. Chem.

(2012)

R. Ye

Biochemical analysis of the canonical model for the mammalian circadian clock

J. Biol. Chem.

(2011)

Z. Wang

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Cell Res.

(2012)

A. Czarna

Quantitative analyses of cryptochrome-mBMAL1 interactions: mechanistic insights into the transcriptional regulation of the mammalian circadian clock

J. Biol. Chem.

(2011)

S. Siepka

Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression

Cell

(2007)

A. Czarna

Structures of Drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function

Cell

(2013)

M. Doi

Circadian regulator CLOCK is a histone acetyltransferase

Cell

(2006)

J-P. Etchegaray

The polycomb group protein EZH2 is required for mammalian circadian clock function

J. Biol. Chem.

(2006)

Y. Nakahata

The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control

Cell

(2008)

A. Raj et al.

Nature, nurture, or chance: stochastic gene expression and its consequences

Cell

(2008)

D. Suter

Origins and consequences of transcriptional discontinuity

Curr. Opin. Cell Biol.

(2011)

L. Motta-Mena

The three Rs of transcription: recruit, retain, and recycle

Mol. Cell

(2010)

G. Asher

Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding

Cell

(2010)

C. Peek

Nutrient sensing and the circadian clock

Trends Endocrinol. Metab.

(2012)

J. Baggs et al.

Nocturnin, a deadenylase in Xenopus laevis retina: a mechanism for posttranscriptional control of circadian-related mRNA

Curr. Biol.

(2003)

N. Douris

Nocturnin regulates circadian trafficking of dietary lipid in intestinal enterocytes

Curr. Biol.

(2011)

P. Lowrey et al.

Mammalian circadian biology: elucidating genome-wide levels of temporal organization

Annu. Rev. Genomics Hum. Genet.

(2004)

T.H. Kang

Circadian oscillation of nucleotide excision repair in mammalian brain

Proc. Natl. Acad. Sci. U.S.A.

(2009)

T-H. Kang

Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase

Proc. Natl. Acad. Sci. U.S.A.

(2010)

C. Ko et al.

Molecular components of the mammalian circadian clock

Hum. Mol. Genet.

(2006)

E. Buhr

Temperature as a universal resetting cue for mammalian circadian oscillators

Science

(2010)

C. Dibner

The mammalian circadian timing system: organization and coordination of central and peripheral clocks

Annu. Rev. Physiol.

(2010)

S-H. Yoo

PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues

Proc. Natl. Acad. Sci. U.S.A.

(2004)

M. Ralph

Transplanted suprachiasmatic nucleus determines circadian period

Science

(1990)

X. Yang

Nuclear receptors, metabolism, and the circadian clock

Cold Spring Harb. Symp. Quant. Biol.

(2007)

C. Saini

Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators

Genes Dev.

(2012)

M. Stratmann et al.

Properties, entrainment, and physiological functions of mammalian peripheral oscillators

J. Biol. Rhythms

(2006)

H. Cho

Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β

Nature

(2012)

J. DeBruyne

CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock

Nat. Neurosci.

(2007)

A. Liu

Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms

PLoS Genet.

(2008)

R. Kondratov

Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock

Genes Dev.

(2006)

E. McDearmon

Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice

Science

(2006)

Y. Sun

The mortality of MOP3 deficient mice with a systemic functional failure

J. Biomed. Sci.

(2006)

B. Cheng

Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis

Proc. Natl. Acad. Sci. U.S.A.

(2011)

K. Lamia

Physiological significance of a peripheral tissue circadian clock

Proc. Natl. Acad. Sci. U.S.A.

(2008)

B. Marcheva

Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes

Nature

(2010)

Cited by (982)

Chronic sleep fragmentation reduces left ventricular contractile function and alters gene expression related to innate immune response and circadian rhythm in the mouse heart
2024, Gene
Sleep disorders have emerged as a widespread public health concern, primarily due to their association with an increased risk of developing cardiovascular diseases. Our previous research indicated a potential direct impact of insufficient sleep duration on cardiac remodeling in children and adolescents. Nevertheless, the underlying mechanisms behind the link between sleep fragmentation (SF) and cardiac abnormalities remain unclear. In this study, we aimed to investigate the effects of SF interventions at various life stages on cardiac structure and function, as well as to identify genes associated with SF-induced cardiac dysfunction. To achieve this, we established mouse models of chronic SF and two-week sleep recovery (SR). Our results revealed that chronic SF significantly compromised left ventricular contractile function across different life stages, leading to alterations in cardiac structure and ventricular remodeling, particularly during early life stages. Moreover, microarray analysis of mouse heart tissue identified two significant modules and nine hub genes (Ddx60, Irf9, Oasl2, Rnf213, Cmpk2, Stat2, Parp14, Gbp3, and Herc6) through protein–protein interaction analysis. Notably, the interactome predominantly involved innate immune responses. Importantly, all hub genes lost significance following SR. The second module primarily consisted of circadian clock genes, and real-time PCR validation demonstrated significant upregulation of Arntl, Dbp, and Cry1 after SF, while subsequent SR restored normal Arntl expression. Furthermore, the expression levels of four hub genes (Ddx60, Irf9, Oasl2, and Cmpk2) and three circadian clock genes (Arntl, Dbp, and Cry1) exhibited correlations with structural and functional echocardiographic parameters. Overall, our findings suggest that SF impairs left ventricular contractile function and ventricular remodeling during early life stages, and this may be mediated by modulation of the innate immune response and circadian rhythm. Importantly, our findings suggest that a short period of SR can alleviate the detrimental effects of SF on the cardiac immune response, while the influence of SF on circadian rhythm appears to be more persistent. These findings underscore the importance of good sleep for maintaining cardiac health, particularly during early life stages.
Melatonin ameliorates hepatic fibrosis via the melatonin receptor 2-mediated upregulation of BMAL1 and anti-oxidative enzymes
2024, European Journal of Pharmacology
Hepatic fibrosis, when left untreated, causes serious health problems that progress to cirrhosis and, in some cases, liver cancer. Activation of hepatic stellate cells may be a key characteristic in the development of hepatic fibrosis. Melatonin, a pineal hormone, exerts anti-fibrotic effects; however, the exact mechanisms remain unclear. In this study, the beneficial effects of melatonin against hepatic fibrosis and the underlying mechanisms were investigated using the human hepatic stellate cell line, LX-2, and in vivo murine animal models. The results showed that melatonin suppressed the expression of transforming growth factor (TGF)-β1-induced fibrosis markers and production of reactive oxygen species in LX-2 cells. Either 4-phenyl-2-propionamidotetralin, a melatonin receptor 2 selective antagonist, or melatonin receptor 2 small interfering RNA abolished the suppressive effects of melatonin, suggesting the involvement of melatonin receptor 2 in melatonin-induced anti-fibrotic and anti-oxidative actions. Melatonin increased the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), a positive circadian clock gene. BMAL1 knockdown reduced the anti-fibrotic and anti-oxidative effects of melatonin, demonstrating the protective effects of melatonin against TGF-β1-induced hepatic stellate cell activation by exhibiting melatonin receptor 2-BMAL1-anti-oxidative effects. In high-fat diet-induced and carbon tetrachloride-induced hepatic fibrosis models, oral melatonin administration decreased the expression of hepatic fibrosis markers and increased the expression of messenger RNA and levels of proteins of BMAL1 and melatonin receptor 2. Thus, melatonin exerted protective effects against hepatic fibrosis through melatonin receptor 2 activation, followed by an upregulation of the BMAL1-anti-oxidative enzyme pathways.
PER2 gene and its association with sleep-related disorders: A review
2024, Physiology and Behavior
The natural circadian rhythm in an individual governs the sleep-wake cycle over 24 h. Disruptions in this internal cycle can lead to major health hazards and sleep disorders. Reports suggest that at least 50 % of people worldwide suffer from sleep-related disorders. An increase in screen time, especially in the wake of the COVID-19 pandemic, is one of the external causative factors for this condition. While many factors govern the circadian clock and its aberrance, the PER2 gene has been strongly linked to chronotypes by many researchers. The current paper provides an extensive examination of key Single Nucleotide Polymorphisms within the PER2 gene and their potential connection to four major types of sleep disorders. This study investigates whether these SNPs play a causative role in sleep disorders or if they are solely associated with these conditions. Additionally, we explore whether these genetic variations exert a lifelong influence on these sleep patterns or if external triggers contribute to the development of sleep disorders. This gene is a crucial regulator of the circadian cycle responsible for the transcription of other clock genes. It regulates a variety of physiological systems such as metabolism, sleep, body temperature, blood pressure, endocrine, immunological, cardiovascular, and renal function. We aim to establish some clarity to the multifaceted nature of this gene, which is often overlooked, and seek to establish the mechanistic role of PER2 gene mutations in sleep disorders. This will improve further understanding, assessment, and treatment of these conditions in future.
Functional interaction of Clock genes and bone morphogenetic proteins in the adrenal cortex
2024, Vitamins and Hormones
The bone morphogenetic protein (BMP) system in the adrenal cortex plays modulatory roles in the control of adrenocortical steroidogenesis. BMP-6 enhances aldosterone production by modulating angiotensin (Ang) II-mitogen-activated protein kinase (MAPK) signaling, whereas activin regulates the adrenocorticotropin (ACTH)-cAMP cascade in adrenocortical cells. A peripheral clock system in the adrenal cortex was discovered and it has been shown to have functional roles in the adjustment of adrenocortical steroidogenesis by interacting with the BMP system. It was found that follistatin, a binding protein of activin, increased Clock mRNA levels, indicating an endogenous function of activin in the regulation of Clock mRNA expression. Elucidation of the interrelationships among the circadian clock system, the BMP system and adrenocortical steroidogenesis regulated by the hypothalamic-pituitary-adrenal (HPA) axis would lead to an understanding of the pathophysiology of adrenal disorders and metabolic disorders and the establishment of better medical treatment from the viewpoint of pharmacokinetics.
Circadian regulated control of myocardial ischemia-reperfusion injury
2024, Trends in Cardiovascular Medicine
Circadian mechanisms have been associated with the pathogenesis of a variety of cardiovascular diseases, including myocardial ischemia-reperfusion injury (I-R). Myocardial ischemia resulting from impaired oxygen delivery to cardiac muscle sets into motion a cascade of cellular events that paradoxically triggers greater cardiac dysfunction upon reinstitution of coronary blood supply, a phenomenon known as I-R. I-R injury has been attributed to a number of cellular defects including increased reactive oxygen species (ROS), increased intracellular calcium and impaired mitochondrial bioenergetics that ultimately lead to cardiac cell death, ventricular remodeling and heart failure. Emerging evidence has identified a strong correlation between cellular defects that underlie I-R and the disrupted circadian. In fact, recent studies have shown that circadian dysfunction exacerbates cardiac injury following MI from impaired cellular quality control mechanisms such as autophagy, which are vital in the clearance of damaged cellular proteins and organelles such as mitochondria from the cell. The accumulation of cellular debris is posited as the central underlying cause of excessive cardiac cell death and ventricular dysfunction following MI.
The complexities that govern the interplay between circadian biology and I-R injury following MI is at its infancy and understanding how circadian misalignment, such as in shift workers impacts I-R injury is of great scientific and clinical importance toward development of new therapeutic strategies using chronotherapy and circadian regulation to mitigate cardiac injury and improve cardiac outcomes after injury. In this review, we highlight recent advances in circadian biology and adaptive cellular quality control mechanisms that influence cardiac injury in response to MI injury with a specific focus on how circadian biology can be utilized to further cardiovascular medicine and patient care.
Is part-night lighting a suitable mitigation strategy to limit Artificial Light at Night effects on the biological rhythm at the behavioral and molecular scales of the oyster Crassostrea gigas?
2023, Science of the Total Environment
Artificial Light at Night (ALAN) is a fast-spreading threat to organisms, especially in coastal environments, where night lighting is increasing due to constant anthropization. Considering that ALAN affects a large diversity of coastal organisms, finding efficient solutions to limit these effects is of great importance but poorly investigated. The potential benefit of one strategy, in particular, should be studied since its use is growing: part-night lighting (PNL), which consists in switching off the lights for a few hours during nighttime. The aim of this study is to investigate the positive potential of the PNL strategy on the daily rhythm of the oyster Crassostrea gigas, a key species of coastal areas of ecological and commercial interest. Oysters were exposed to a control condition and three different ALAN modalities. A realistic PNL condition is applied, recreating a strategy of city policy in a coastal city boarding an urbanized bay (Lanton, Arcachon Bay, France). The PNL modality consists in switching off ALAN direct sources (5 lx) for 4 h (23−3 h) during which oysters are in darkness. Then, a PNL + skyglow (PNL + S) modality reproduces the previous one mimicking a skyglow (0.1 lx), an indirect ALAN source, during the direct lighting switch off, to get as close as possible to realistic conditions. Finally, the third ALAN condition mimics full-night direct lighting (FNL). Results revealed that PNL reduces some adverse effects of FNL on the behavioral daily rhythm. But, counterintuitively, PNL + S appears more harmful than FNL for some parameters of the behavioral daily rhythm. PNL + S modality is also the only one that affect oysters' clock and melatonin synthesis gene expression, suggesting physiological consequences. Thus, in realistic conditions, the PNL mitigation strategy might not be beneficial in the presence of skyglow, seeing worse for a coastal organism such as the oysters.

View all citing articles on Scopus

View full text

Trends in Cell Biology

ReviewMolecular architecture of the mammalian circadian clock

Highlights

Section snippets

A clockwork physiology

A hierarchical timing system

Peripheral clocks regulate tissue-specific expression patterns

Insight into the molecular clock mechanism

Post-transcriptional/translational control of circadian output

Concluding remarks

Acknowledgments

Glossary

Trends Neurosci.

Cell

Curr. Biol.

Neuron

J. Biol. Chem.

Cell

Cell

Cell Metab.

Cell

Curr. Biol.

Cell Metab.

Dev. Cell

Mol. Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell Res.

J. Biol. Chem.

Cell

Cell

Cell

J. Biol. Chem.

Cell

Cell

Curr. Opin. Cell Biol.

Mol. Cell

Cell

Trends Endocrinol. Metab.

Curr. Biol.

Curr. Biol.

Mammalian circadian biology: elucidating genome-wide levels of temporal organization

Annu. Rev. Genomics Hum. Genet.

Circadian oscillation of nucleotide excision repair in mammalian brain

Proc. Natl. Acad. Sci. U.S.A.

Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase

Proc. Natl. Acad. Sci. U.S.A.

Molecular components of the mammalian circadian clock

Hum. Mol. Genet.

Temperature as a universal resetting cue for mammalian circadian oscillators

Science

The mammalian circadian timing system: organization and coordination of central and peripheral clocks

Annu. Rev. Physiol.

PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues

Proc. Natl. Acad. Sci. U.S.A.

Transplanted suprachiasmatic nucleus determines circadian period

Science

Nuclear receptors, metabolism, and the circadian clock

Cold Spring Harb. Symp. Quant. Biol.

Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators

Genes Dev.

Properties, entrainment, and physiological functions of mammalian peripheral oscillators

J. Biol. Rhythms

Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β

Nature

CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock

Nat. Neurosci.

Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms

PLoS Genet.

Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock

Genes Dev.

Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice

Science

The mortality of MOP3 deficient mice with a systemic functional failure

J. Biomed. Sci.

Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis

Proc. Natl. Acad. Sci. U.S.A.

Physiological significance of a peripheral tissue circadian clock

Proc. Natl. Acad. Sci. U.S.A.

Review
Molecular architecture of the mammalian circadian clock