BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis

Welz, Patrick-Simon; Zinna, Valentina M.; Symeonidi, Aikaterini; Koronowski, Kevin B.; Kinouchi, Kenichiro; Smith, Jacob G.; Guillén, I.; Castellanos, Andrés; Furrow, Stephen; Aragón, Ferrán; Crainiciuc, Georgiana; Prats, Neus; Caballero, Juan; Hidalgo, Andrés; Sassone–Corsi, Paolo; Benitah, Salvador Aznar

doi:10.1016/j.cell.2019.05.009

Cited by 117 publications

(84 citation statements)

References 51 publications

(68 reference statements)

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“…To further dissect the interplay between central and peripheral clocks, the groups of Paolo Sassone‐Corsi and Salvador Aznar Benitah created a mouse model in which Bmal1 expression (and, thus, clock function) can be restored in a specific tissue in an otherwise Bmal1 ‐deficient animal by expression of CRE recombinase. [ 64 ] In the resulting tissue clock rescue model, expressing functional BMAL1 only in the epidermis, an oscillation of the epidermal clock machinery was observed with a preserved phase, but a slight reduction in amplitude compared to wildtype animals under light–dark conditions. [ 64 ] In DD however, rescue mice lose their rhythmic regulation completely, emphasising that the epidermis requires light—or another light‐driven signal—as a synchronizer of tissue physiology.…”

Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

“…[ 64 ] In the resulting tissue clock rescue model, expressing functional BMAL1 only in the epidermis, an oscillation of the epidermal clock machinery was observed with a preserved phase, but a slight reduction in amplitude compared to wildtype animals under light–dark conditions. [ 64 ] In DD however, rescue mice lose their rhythmic regulation completely, emphasising that the epidermis requires light—or another light‐driven signal—as a synchronizer of tissue physiology. [ 64 ] For the epidermis it remains a possibility that light directly synchronises the clock via detection by keratinocytes, but this cannot be a generalised mechanism because comparable characteristics were observed for the liver and adrenal transplants that are not subject to direct light exposure.…”

Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

“…[ 64 ] In DD however, rescue mice lose their rhythmic regulation completely, emphasising that the epidermis requires light—or another light‐driven signal—as a synchronizer of tissue physiology. [ 64 ] For the epidermis it remains a possibility that light directly synchronises the clock via detection by keratinocytes, but this cannot be a generalised mechanism because comparable characteristics were observed for the liver and adrenal transplants that are not subject to direct light exposure. [ 44,64,65 ] Together, these data show that—at least under rhythmic environmental conditions—peripheral clocks are sufficient to drive physiological tissue rhythms.…”

Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

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The Tissue Clock Network: Driver and Gatekeeper of Circadian Physiology

Harder

Oster

2020

BioEssays

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In mammals, a network of cellular circadian clocks organizes physiology and behavior along the 24-h day cycle. The traditional hierarchical model of circadian clock organization with a central pacemaker and peripheral slave oscillators has recently been challenged by studies combining tissue-specific mouse mutants with transcriptome analyses. First, a surprisingly small number of tissue rhythms are lost when only local clocks are ablated and, second, transcriptional circadian rhythms appear to be regulated by a complex mix of local and systemic factors. As reviewed here, these findings suggest a more integrated model of clock network interaction with the central pacemaker as the main source of behavioral and systemic-physiological rhythms and peripheral clocks controlling some local rhythms while at the same time acting as gatekeepers that temporally adjust cellular responses to external stimuli.

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Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

Section: Tissue Clock Rescue Reveals Local Clock‐dependent and ‐Indepmentioning

confidence: 99%

See 1 more Smart Citation

The Tissue Clock Network: Driver and Gatekeeper of Circadian Physiology

Harder

Oster

2020

BioEssays

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“…60,61 Two recent studies also showed that peripherical clocks can be synchronized by light independently of a functional central circadian clock, and suggested that phototransduction players could drive it. 62,63 Clock genes and circadian oscillation have been shown to regulate the EMT program, 13,64 which is one of the mechanisms behind the spread and colonisation of tumour cells 23,65 . Our differential gene expression analysis of primary tumours revealed an elevated expression of genes associated with EMT in CRD.…”

Section: Discussionmentioning

confidence: 99%

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

Hadadi

Taylor

et al. 2019

Preprint

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Breast cancer is the most common type and one of the major causes of cancer death in woman worldwide. Epidemiological studies have established a link between night shift work and increased cancer risk, suggesting that circadian disruption may interfere with carcinogenesis. We aim to shed light on the effect of chronic jetlag on mammary tumour development. Therefore, we used a mouse model of spontaneous mammary tumorigenesis that we exposed to chronic circadian disruption. We observed that circadian disruption significantly increases cancer cell dissemination and metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. We finally showed that all these defects can be corrected by the use of a CXCR2 inhibitor. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

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“…Loss of microbiota was also shown to change rhythmic gene expression within the mouse intestinal transcriptome while leaving behavioral rhythms intact 25 . Notably, the recent development of tissue specific conditional Bmal1 rescue mice was instrumental in uncovering intact peripheral circadian rhythms in the skin epidermis and liver in the absence of circadian signaling from the SCN 26 . These data highlight the importance of peripheral clocks and their ability to process input signals from local factors.…”

Section: Introductionmentioning

confidence: 99%

Ontogeny and function of the circadian clock in intestinal organoids

Rosselot

Park

Matsuura

et al. 2020

Preprint

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Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed molecular mechanisms regulating circadian physiology of the intestine remain largely unknown. The lack of appropriate human model systems that enable organ-and/or diseasespecific interrogation of clock functions is a major obstacle hindering advancements of translational applications using chronotherapy. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids (HIEs) possess robust circadian rhythms, and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses. RNA-Seq data show ~4% of genes are rhythmically expressed in HIEs. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids. Importantly, the observed circadian time-dependent necrotic cell death response is abolished in both mouse enteroids and human intestinal organoids (HIOs) lacking robust circadian rhythms. Our findings uncover robust functions of circadian rhythms regulating critical clockcontrolled genes (CCGs) in human enteroids governing organism-specific, circadian phasedependent necrotic cell death responses. Our data highlight unique differences between mouse and human enteroids, and lay a foundation for human organ-and disease-specific investigation of clock functions using human organoids for translational applications.

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis

Cited by 117 publications

References 51 publications

The Tissue Clock Network: Driver and Gatekeeper of Circadian Physiology

The Tissue Clock Network: Driver and Gatekeeper of Circadian Physiology

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

Ontogeny and function of the circadian clock in intestinal organoids

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