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The emergence of circadian timekeeping in the intestine
Circadian rhythms are present in cells throughout the body but how these develop is poorly understood. Here, using Drosophila genetics and single cell analysis, authors find that the intestinal clock emerges after development is complete, and that differentiation disrupts its function.
- Kathyani Parasram
- , Amy Zuccato
- & Phillip Karpowicz
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Article
| Open Access
Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
It has been reported that the circadian clock regulator Bmal1 can modulate tumorigenesis. Here the authors show that ectopic expression of Bmal1 promotes an immune resistant mesenchymal melanoma cell state associated with increased AP-1 activity.
- Xue Zhang
- , Shishir M. Pant
- & Chi V. Dang
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Article
| Open Access
Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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| Open Access
Multi-omics profiling reveals rhythmic liver function shaped by meal timing
Post-translational modifications (PTMs) couple feed-fast cycles to circadian clocks. Here, the authors systematically profile daily rhythms of the proteome, 4 PTMs and lipidome in mouse livers under TRF, providing a comprehensive resource detailing rhythmic liver functions shaped by meal timing.
- Rongfeng Huang
- , Jianghui Chen
- & Min-Dian Li
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Article
| Open Access
Singularity response reveals entrainment properties in mammalian circadian clock
Current methods to assess circadian biological parameters can be labor intensive. Here, the authors establish a method for estimating circadian entrainment characteristics using simple experiments and mathematical modeling, revealing the responsiveness of circadian rhythms to diverse stimuli in the mammalian circadian clock.
- Kosaku Masuda
- , Naohiro Kon
- & Arisa Hirano
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The rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice
Many transcriptomic pathways in the liver show circadian rhythms, which have been reported to be disrupted in aged mice. Here the authors report that the expression of transcription factor Egr-1 decreases and its rhythm is shifted with age in the liver of male mice, and that deletion of Egr-1 results in increased liver fat accumulation.
- Jing Wu
- , Dandan Bu
- & Chao-Jun Li
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Article
| Open Access
Influence of circadian clocks on adaptive immunity and vaccination responses
Circadian rhythms have been shown to influence immune responses, but it is unclear whether this influences responses to vaccines. Here the authors show that dendritic cells migrate in a circadian rhythm meaning that interactions with T cells are altered leading to differential vaccine responses.
- Louise Madeleine Ince
- , Coline Barnoud
- & Christoph Scheiermann
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| Open Access
The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing
Circadian rhythms are known to impact a range of biological processes including in the immune system. Here the authors show how circadian rhythms modulate the T cell response to vaccination via regulation of dendritic cell metabolism.
- Mariana P. Cervantes-Silva
- , Richard G. Carroll
- & Annie M. Curtis
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| Open Access
Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
Cryptochromes are transcriptional regulators of the circadian clock in mammals, and genetic loss of cryptochromes reduces p53-associated cancer risk in mice. Here the authors report the discovery of small molecule M47, which destabilizes cryptochrome 1 and extends the lifespan of p53 knock-out mice.
- Seref Gul
- , Yasemin Kubra Akyel
- & Ibrahim Halil Kavakli
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Tempo: an unsupervised Bayesian algorithm for circadian phase inference in single-cell transcriptomics
Previous efforts to study the circadian clock using scRNA-seq have relied on time course designs that treat cell collection time as a proxy for circadian time. Here, the authors introduce a statistical method to infer circadian timing directly from expression, enabling researchers to study circadian phase heterogeneity.
- Benjamin J. Auerbach
- , Garret A. FitzGerald
- & Mingyao Li
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| Open Access
Aschoff’s rule on circadian rhythms orchestrated by blue light sensor CRY2 and clock component PRR9
Circadian pace is modulated by light intensity. Here the authors show that CRY2 interacts with PRR9 to mediate blue light input to the circadian clock and is degraded at higher light intensity offering a mechanistic explanation as to how intensity can modify clock place.
- Yuqing He
- , Yingjun Yu
- & Lei Wang
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Article
| Open Access
Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals
The mammalian circadian clock is composed of clock genes forming transcriptional feedback loops. Here, the authors identify a key role of the secondary feedback loop that is interlocked with the core loop to establish a perturbation-resilient clock system.
- Yasuko O. Abe
- , Hikari Yoshitane
- & Yoshitaka Fukada
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Article
| Open Access
Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα
Hyperimmunity is associated with Alzheimer disease. Here the authors show that the Presenilin 2 N141I mutation causes overproduction of clock-controlled cytokines and memory deficits through suppression of REV-ERBα gene by hypermethylation.
- Hyeri Nam
- , Younghwan Lee
- & Seong-Woon Yu
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HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape
Genome-wide occupancy of the master circadian clock transcription factor BMAL1::CLOCK varies across tissues and is reprogrammed in cancers, but how specificity is governed is not known. Here the authors show BMAL1::CLOCK in liver tissue is guided by chromatin accessibility remodeled by HNF4A, shedding new lights onto mechanisms of dysregulated circadian rhythms in hepatocarcinoma.
- Meng Qu
- , Han Qu
- & Steve A. Kay
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Synchronization between peripheral circadian clock and feeding-fasting cycles in microfluidic device sustains oscillatory pattern of transcriptome
Chronic desynchronization between physiological and behavioral rhythms has been linked to the onset of metabolic diseases. Here the authors control the cyclic metabolic signals in a microfluidic device to study the effects of the timing, period and frequency of glucose and insulin on the transcriptome of cultured fibroblasts.
- Onelia Gagliano
- , Camilla Luni
- & Nicola Elvassore
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| Open Access
Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology
Osmotic compensation by electroneutral ion transport buffers TORC1-mediated changes in the cytosolic proteome, and maintains intracellular homeostasis and cell volume over the circadian cycle. Here, the authors find such ion content changes drive daily rhythms in cardiomyocyte electrical activity.
- Alessandra Stangherlin
- , Joseph L. Watson
- & John S. O’Neill
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| Open Access
Circa-SCOPE: high-throughput live single-cell imaging method for analysis of circadian clock resetting
Phase Transition Curves (PTCs) describe phase shifts of circadian oscillations due to a stimulus and they are important for studying circadian clock resetting. Here, the authors present a method for high-throughput reconstruction of PTCs using fluorescent live imaging and single-cell analysis.
- Gal Manella
- , Dan Aizik
- & Gad Asher
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Article
| Open Access
Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding
Tissue circadian clocks contribute to the regulation of physiology and metabolism. Here the authors investigate the role of the intestinal circadian clock in energy homeostasis and show that the intestinal clock acts as an accelerator in dietary fat absorption.
- Fangjun Yu
- , Zhigang Wang
- & Baojian Wu
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Article
| Open Access
Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis
Alteration of circadian rhythms is often observed in patients with chronic kidney disease (CKD). Here, the authors show that CKD-induced dysfunction of the circadian clock increases the expression of G protein-coupled receptor 68 in circulating monocytes and that their cardiac infiltration exacerbates inflammation and fibrosis of heart.
- Yuya Yoshida
- , Naoya Matsunaga
- & Shigehiro Ohdo
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| Open Access
Circadian clock dysfunction in human omental fat links obesity to metabolic inflammation
Whether chronic inflammation contributes to metabolic disease through the dysregulation of circadian systems remains incompletely understood in humans. Here the authors show that circadian clock function is perturbed in adipose tissue from individuals with obesity, and that inhibition of NFkB improves clock function.
- Eleonore Maury
- , Benoit Navez
- & Sonia M. Brichard
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| Open Access
A circadian clock regulates efflux by the blood-brain barrier in mice and human cells
The blood-brain barrier is critical for neural function. Here, the authors show that efflux of xenobiotics through the BBB follows a circadian rhythm in mice and human cells.
- Shirley L. Zhang
- , Nicholas F. Lahens
- & Amita Sehgal
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| Open Access
Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells
Red blood cells, which do not possess a nucleus, have circadian redox rhythms with incompletely understood regulatory mechanisms. Here the authors show that glucose metabolism plays a crucial role in regulating circadian redox status of human red blood cells.
- Ratnasekhar Ch
- , Guillaume Rey
- & Akhilesh B. Reddy
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Article
| Open Access
Data-independent acquisition method for ubiquitinome analysis reveals regulation of circadian biology
Protein ubiquitylation is often studied by proteomics but how data independent acquisition (DIA) may advance these studies remains to be explored. Here, the authors show that DIA improves ubiquitylation site identification and quantification, enabling them to characterize the circadian ubiquitinome in human cells.
- Fynn M. Hansen
- , Maria C. Tanzer
- & Matthias Mann
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| Open Access
Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation
Drugs of abuse have been shown to perturb circadian rhythms. Here, the authors show in mice that cocaine exposure modulates circadian gene expression in the striatum through a previously unappreciated pathway that involves dopamine D2 receptors and the nuclear receptor PPARγ.
- Karen Brami-Cherrier
- , Robert G. Lewis
- & Emiliana Borrelli
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| Open Access
Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice
Circadian disruption is implicated in the development of different human cancers. Here the authors show that chronic circadian disruption, through continuous jet lag, only moderately affects primary tumour growth but promotes cancer-cell dissemination and metastasis in a mouse model of spontaneous mammary tumorigenesis.
- Eva Hadadi
- , William Taylor
- & Hervé Acloque
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Article
| Open Access
Malaria parasites regulate intra-erythrocytic development duration via serpentine receptor 10 to coordinate with host rhythms
The mechanism underlying periodicity of Plasmodium’s intra-erythrocytic developmental cycle (IDC) is unclear. Here, Subudhi et al. show that serpentine receptor 10 (SR10) plays a role in regulating the schedule of the IDC in line with the timing of host daily rhythms.
- Amit K. Subudhi
- , Aidan J. O’Donnell
- & Arnab Pain
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| Open Access
Damped circadian oscillation in the absence of KaiA in Synechococcus
Proteins KaiA, KaiB and KaiC constitute a biochemical circadian oscillator in Synechococcus cyanobacteria. Here, Kawamoto et al. show that kaiBC promoter activity exhibits a damped, low-amplitude circadian oscillation in the absence of KaiA, which could explain the circadian rhythms observed in other bacteria that lack a kaiA homologue.
- Naohiro Kawamoto
- , Hiroshi Ito
- & Hideo Iwasaki
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Circadian regulation of mitochondrial uncoupling and lifespan
Disruption of different components of molecular circadian clocks has varying effects on health and lifespan of model organisms. Here the authors show that loss of period extends life in drosophila melanogaster.
- Matt Ulgherait
- , Anna Chen
- & Mimi Shirasu-Hiza
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| Open Access
Regulatory T cells confer a circadian signature on inflammatory arthritis
Circadian rhythms can alter inflammatory state and activity of inflammatory diseases such as rheumatoid arthritis. Here the authors show that extrinsic signals confer a circadian rhythm to regulatory T cell activity, which in turn drives rhythmic inflammation in collagen-induced arthritis.
- L. E. Hand
- , K. J. Gray
- & J. E. Gibbs
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| Open Access
The circadian clock and darkness control natural competence in cyanobacteria
The cyanobacterium Synechococcus elongatus is a model organism for the study of circadian rhythms, and is naturally competent for transformation. Here, Taton et al. identify genes required for natural transformation in this organism, and show that the coincidence of circadian dusk and darkness regulates the competence state in different day lengths.
- Arnaud Taton
- , Christian Erikson
- & Susan S. Golden
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The tight junction protein TJP1 regulates the feeding-modulated hepatic circadian clock
The circadian clock regulates rhythms of physiology and metabolism in response to environmental cues such as food intake. Here, the authors show that tight junction protein 1 (TJP1) interacts with period 1 and modulates its nuclear translocation in a mTOR-dependent manner.
- Yi Liu
- , Yuanyuan Zhang
- & Yiguo Wang
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Article
| Open Access
FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora
Circadian clocks control daily rhythms of molecular and physiological activities. Here, the authors show that the interaction between proteins FRQ and CK1, rather than FRQ stability, is a major rate-limiting step in circadian period determination in the model fungus Neurospora.
- Xiao Liu
- , Ahai Chen
- & Yi Liu
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Article
| Open Access
Circadian control of lung inflammation in influenza infection
The circadian clock affects immune responses, but its role in influenza infection is not well understood. Here, Sengupta et al. show that time of infection and the circadian clock have no effect on lung virus titers, but affect inflammation, morbidity and mortality.
- Shaon Sengupta
- , Soon Y. Tang
- & Garret A. FitzGerald
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| Open Access
Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption
Time-restricted feeding (TRF) has beneficial metabolic effects. Here the authors examine how TRF impacts muscle physiology using fly models of metabolically adverse conditions, including diet and genetic models of obesity as well as circadian rhythm disruption, and find that TRF ameliorates skeletal muscle dysfunction.
- Jesús E. Villanueva
- , Christopher Livelo
- & Girish C. Melkani
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| Open Access
Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity
The circadian transcription factors BMAL1:CLOCK bind to E/E′-boxes in gene regulatory elements of their targets and facilitate rhythmic expression. Here, the authors mutate the Per2 promoter E’′-box in mice and observe that cell- and tissue-autonomous oscillations are dampened and that animals are less susceptible to jet lag.
- Masao Doi
- , Hiroyuki Shimatani
- & Hitoshi Okamura
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Perspective
| Open Access
Continuous dynamic adjustment of the plant circadian oscillator
Biological circadian rhythms maintain a period close to 24 h in coordination with the Earth’s fixed rotational period. Here Webb et al. discuss how external cues continuously adjust phase and period, viewing the oscillator as a dynamically-adjusted plastic system rather than tightly-coupled cogs in a mechanical clock.
- Alex A. R. Webb
- , Motohide Seki
- & Camila Caldana
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| Open Access
The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication
The circadian clock can affect pathogen replication, but underlying molecular mechanisms are unclear. Here the authors demonstrate that the circadian components BMAL1 and REV-ERBα affect entry of hepatitis C virus (HCV) into hepatocytes and genome replication of HCV and related flaviviruses dengue and zika.
- Xiaodong Zhuang
- , Andrea Magri
- & Jane A. McKeating
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| Open Access
Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma
Hepatocyte nuclear factor 4 alpha (HNF4α) is regulated by different promoters to generate two isoforms, one of which functions as a tumor suppressor. Here, the authors reveal that induction of the alternative isoform in hepatocellular carcinoma inhibits the circadian clock by repressing BMAL1, and the reintroduction of BMAL1 prevents HCC tumor growth.
- Baharan Fekry
- , Aleix Ribas-Latre
- & Kristin Eckel-Mahan
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Article
| Open Access
REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis
REV-ERBα is a nuclear receptor that links the circadian pathways with those of metabolism. Here the authors show REV-ERBα is also involved with linking the circadian system with the inflammatory pathways of an experimental model of colitis through regulation of the NF-κB/NLRP3 axis.
- Shuai Wang
- , Yanke Lin
- & Baojian Wu
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Article
| Open Access
Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging
While epigenetic factors have been implicated in the circadian rhythm, the detection of circadian cytosine modifications has remained elusive. Here the authors identify a large number of epigenetically variable cytosines that show circadian oscillations in their modification status in mice.
- Gabriel Oh
- , Sasha Ebrahimi
- & Art Petronis
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Article
| Open Access
Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
Circadian clock regulates hepatic gene expression and functions. Here Chao et al. show that alteration of circadian clock genes by Period deletion induces polyploidy in hepatocytes due to impaired regulation of Erk signaling by mitogen-activated protein kinase phosphatase 1.
- Hsu-Wen Chao
- , Masao Doi
- & Hitoshi Okamura
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Article
| Open Access
Rhythmic potassium transport regulates the circadian clock in human red blood cells
Circadian rhythms usually rely on cyclic variations in gene expression. Red blood cells, however, display circadian rhythms while being devoid of nuclear DNA. Here, Henslee and colleagues show that circadian rhythms in isolated human red blood cells are dependent on rhythmic transport of K+ ions.
- Erin A. Henslee
- , Priya Crosby
- & Fatima H. Labeed
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Article
| Open Access
Misalignment with the external light environment drives metabolic and cardiac dysfunction
The misalignment between internal circadian rhythm and the day-night cycle can be caused by genetic, behavioural and environmental factors, and may have a profound impact on human physiology. Here West et al. show that desynchrony between the internal clock and the external environment alter metabolic parameters and cardiac function in mice.
- Alexander C. West
- , Laura Smith
- & David A. Bechtold
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Correspondence
| Open Access
Correspondence: Reply to ‘Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα’
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
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Correspondence
| Open Access
Correspondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα
- Brian J. Altman
- , Annie L. Hsieh
- & Chi V. Dang
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Article
| Open Access
Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling
Core clock genes, such asBmal1, are expressed in astrocytes, but their contribution to the timekeeping system is unknown. Barca-Mayo et al. report that deletion of Bmal1in Glast+ astrocytes alters the neuronal clock through GABA signalling, leading to abnormal circadian locomotor behaviour and impaired cognition in mice.
- Olga Barca-Mayo
- , Meritxell Pons-Espinal
- & Davide De Pietri Tonelli
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Article
| Open Access
Cellular mechano-environment regulates the mammary circadian clock
Circadian clocks regulate physiological and behavioural rhythms. Here, the authors show that the stiffness of the extracellular environment regulates circadian clocks in murine breast epithelium via Rho signalling, and explain how extracellular matrix stiffening in aging affects circadian rhythm, with implication in disease.
- Nan Yang
- , Jack Williams
- & Qing-Jun Meng
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Article
| Open Access
LWD–TCP complex activates the morning gene CCA1 in Arabidopsis
TheArabidopsisCCA1 transcription factor is a core regulator of the circadian clock. Here, the authors show that the LWD1 protein, in complex with the TCP20 or TCP22 transcription factors, acts as a co-activator of CCA1 expression contributing to elevated CCA1 expression at dawn.
- Jing-Fen Wu
- , Huang-Lung Tsai
- & Shu-Hsing Wu
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Article
| Open Access
Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock
The effect of the liver clock is modified by food entrainment via Bmal1/Clock core machinery. Here the authors show that insulin promotes postprandial Akt-dependent phosphorylation of Bmal1, resulting in association with 14-3-3 and Bmal1 shuttling out of the nucleus, thereby disrupting Bmal1 transcriptional effects on the clock.
- Fabin Dang
- , Xiujie Sun
- & Yi Liu
LKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes