Periodicity, repression, and the molecular architecture of the mammalian circadian clock (original) (raw)

Molecular architecture of the mammalian circadian clock

Trends Cell Biol, 2013

Circadian clocks coordinate physiology and behavior with the 24h 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 24h 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.

Transcriptional architecture of the mammalian circadian clock

Nature reviews. Genetics, 2017

Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

Transcriptional architecture and chromatin landscape of the core circadian clock in mammals

Science (New York, N.Y.), 2012

The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale f...

Mammalian Circadian Clock: The Roles of Transcriptional Repression and Delay

Handbook of Experimental Pharmacology, 2013

The circadian clock is an endogenous oscillator with a 24-h period. Although delayed feedback repression was proposed to lie at the core of the clock more than 20 years ago, the mechanism for making delay in feedback repression in clock function has only been demonstrated recently. In the mammalian circadian clock, delayed feedback repression is mediated through E/E 0-box, D-box, and RRE transcriptional cis-elements, which activate or repress each other through downstream transcriptional activators/repressors. Among these three types of cis-elements, transcriptional negative feedback mediated by E/E 0-box plays a critical role for circadian rhythms. A recent study showed that a combination of D-box and RRE elements results in the delayed expression of Cry1, a potent transcriptional inhibitor of the E/E 0-box. The overall interconnection of these cis-elements can be summarized as a combination of two oscillatory motifs: one is a simple delayed feedback repression where only an RRE represses an E/E 0-box, and the other is a repressilator where each element inhibits another in turn (i.e., E/E 0 box represses an RRE, an RRE represses a D-box, and a D-box represses an E/E 0 box). Experimental verification of the roles of each motif as well as post-transcriptional regulation of the circadian oscillator will be the next challenges.

Molecular biological approach to the circadian clock mechanism

Neuroscience Research the Official Journal of the Japan Neuroscience Society, 1995

Many circadian phenomena have been described in a diverse range of species, from single cellular organisms to higher species of plants and animals. From several lines of evidence from Drosophila and Neurospora, the oscillation of the circadian clock seems to involve cycling gene expression. Although a great deal of information concerning the anatomy, neurophysiology and neurochemistry of circadian pacemakers has been obtained over the last decade, molecular and cellular approaches to this problem have only just begun. I will summarize recent progress of the molecular biological approach to the circadian clock mechanism. Finally, the importance of' transcription factors to envision the common mechanism of circadian clock in the diverged species will be discussed considering with the existence of a hypothetical 'Time Box'.

Posttranslational Mechanisms Regulate the Mammalian Circadian Clock

Cell, 2001

and/or BMAL1 to inhibit transcription, forming a nega-1 Department of Neurobiology tive feedback loop (Griffin et al., 1999; Kume et al., 1999; University of Massachusetts Medical School van der Horst et al., 1999; Vitaterna et al., 1999; 55 Lake Avenue North Shearman et al., 2000b). Bmal1 RNA levels are also Worcester, Massachusetts 01655 rhythmic, antiphase to those for the mPer and mCry 2 School of Biological Sciences genes (see Reppert and Weaver, 2001). Genetic data are University of Manchester consistent with a model in which mPER2 rhythmically Oxford Road stimulates Bmal1 transcription, forming a positive feed-Manchester M13 9PT back loop (Zheng et al., 1999; Shearman et al., 2000b). United Kingdom mPER1 appears to influence clock function at a posttranscriptional level through interaction with other circadian regulatory proteins (Bae et al., 2001; Zheng et al., Summary 2001). mPER3 does not have a critical role in the maintenance of the core clock feedback loops, but instead We have examined posttranslational regulation of clock may function as an output signal (Shearman et al., 2000a; proteins in mouse liver in vivo. The mouse PERIOD pro-Bae et al., 2001). Recent in vitro studies suggest that teins (mPER1 and mPER2), CLOCK, and BMAL1 undergo the transcriptional activity of the CLOCK:BMAL1 heterorobust circadian changes in phosphorylation. These prodimer can be modulated directly by nuclear hormone teins, the cryptochromes (mCRY1 and mCRY2), and careceptors and redox potential (McNamara et al., 2001; sein kinase I epsilon (CKI⑀) form multimeric complexes Rutter et al., 2001). that are bound to DNA during negative transcriptional Phosphorylation can determine the cellular location feedback. CLOCK:BMAL1 heterodimers remain bound and stability of clock proteins, and is a critical process to DNA over the circadian cycle. The temporal increase for building time delays into the 24 hr molecular mechain mPER abundance controls the negative feedback innism (Edery et al., 1994; Dunlap, 1999; Young, 2000; teractions. Analysis of clock proteins in mCRY-deficient Denault et al., 2001).

System-level identification of transcriptional circuits underlying mammalian circadian clocks

Nature Genetics, 2005

Mammalian circadian clocks consist of complexly integrated regulatory loops 1-5 , making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits 6 . Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E¢ boxes, DBP/E4BP4 binding elements 7 and RevErbA/ROR binding elements 8 in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E¢ boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E¢ boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.

Structural and functional features of transcription factors controlling the circadian clock

Current Opinion in Genetics & Development, 2005

Most organisms adapt the timing of their physiology to the cyclic changes of the environment with the use of intrinsic timekeeping systems called circadian clocks. Central features of the molecular clock mechanism are transcription-and translation-based negative feedback loops: clock genes and their products interact to generate oscillation of specific transcripts and proteins, and, ultimately, circadian rhythmicity and behavior. Various transcription factors constitute the molecular clock, and the signal transduction cascades governing their function appear to be crucial for the fine-tuning of the circadian cycle.

Molecular components of the circadian clock in mammals

Diabetes, Obesity and Metabolism, 2015

The circadian clock mechanism in animals involves a transcriptional feedback loop in which the bHLH-PAS proteins CLOCK and BMAL1 form a transcriptional activator complex to activate the transcription of the Period and Cryptochrome genes, which in turn feed back to repress their own transcription. In the mouse liver, CLOCK and BMAL1 interact with the regulatory regions of thousands of genes, which are both cyclically and constitutively expressed. The circadian transcription in the liver is clustered in phase and this is accompanied by circadian occupancy of RNA polymerase II recruitment and initiation. These changes also lead to circadian fluctuations in histone H3 lysine4 trimethylation (H3K4me3) as well as H3 lysine9 acetylation (H3K9ac) and H3 lysine27 acetylation (H3K27ac). Thus, the circadian clock regulates global transcriptional poise and chromatin state by regulation of RNA polymerase II.

Molecular components of the mammalian circadian clock

Human Molecular Genetics, 2006

Circadian rhythms are 24-h oscillations in behavior and physiology, which are internally generated and function to anticipate the environmental changes associated with the solar day. A conserved transcriptional -translational autoregulatory loop generates molecular oscillations of 'clock genes' at the cellular level. In mammals, the circadian system is organized in a hierarchical manner, in which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream oscillators in peripheral tissues. Recent findings have revealed that the clock is cell-autonomous and self-sustained not only in a central pacemaker, the SCN, but also in peripheral tissues and in dissociated cultured cells. It is becoming evident that specific contribution of each clock component and interactions among the components vary in a tissue-specific manner. Here, we review the general mechanisms of the circadian clockwork, describe recent findings that elucidate tissue-specific expression patterns of the clock genes and address the importance of circadian regulation in peripheral tissues for an organism's overall well-being.