Extensive tissue-specific expression variation and novel regulators underlying circadian behavior

Litovchenko, Maria; Meireles-Filho, Antonio C. A.; Frochaux, Michael; Bevers, R.; Prunotto, Alessio; Anduaga, Ane Martín; Hollis, Brian; Gardeux, Vincent; Braman, Virginie; Russeil, Julie; Kadener, Sebastián; Peraro, Matteo Dal; Deplancke, Bart

doi:10.1126/sciadv.abc3781

Cited by 26 publications

(28 citation statements)

References 97 publications

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“…In addition to dampening, molecular oscillations of the fat body clock gradually grew out of phase with those of the brain clock over prolonged DD exposure, suggestive of a long free-running period of the fat body clock. Our observation that the fat body clock operates with a long endogenous period is consistent with the finding that expression patterns of clock genes such as tim and per exhibit 26- to 28-h periods in the fat body, as assessed by RNA sequencing of fat body tissue conducted at different time points throughout the day, while the same genes displayed ~24-h oscillations in brain tissue (Litovchenko et al, 2021). This further supports our conclusion that the fat body clock does not impact feeding behavior, since robust ~24-h feeding rhythms persist in flies kept in constant darkness despite the fact that the fat body clocks operate with long periods under these conditions.…”

Section: Discussionsupporting

confidence: 88%

Central and Peripheral Clock Control of Circadian Feeding Rhythms

et al. 2021

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Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

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Section: Discussionsupporting

confidence: 88%

Central and Peripheral Clock Control of Circadian Feeding Rhythms

et al. 2021

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“…Our data from photoreceptors are consistent with Clk:Cyc regulating expression of several important eye-specific TFs in Drosophila photoreceptors, suggesting a mechanism through which Clk and Cyc control expression of many genes indirectly. This is likely a widespread phenomenon across Drosophila tissues because gene regulatory network analysis of cyclic transcripts in brain, gut, Malphigian tubules, and fat bodies also identified many Clock-regulated TFs, including h, hth, Mitf, and GATAd [88].…”

Section: Plos Geneticsmentioning

confidence: 99%

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

et al. 2022

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The aging eye experiences physiological changes that include decreased visual function and increased risk of retinal degeneration. Although there are transcriptomic signatures in the aging retina that correlate with these physiological changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. Here, we integrated ATAC-seq and RNA-seq data to identify 57 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 57 age-regulated transcription factors include two circadian regulators, Clock and Cycle, that showed sustained increased activity during aging. When we disrupted the Clock:Cycle complex by expressing a dominant negative version of Clock (ClkDN) in adult photoreceptors, we observed changes in expression of 15–20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that expression of ClkDN in photoreceptors leads to changes in activity of 37 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, expression of ClkDN in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and Cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.

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“…Furthermore, the GATA motif is necessary for enhancer activity in vivo, as mutating GATA motif in a reporter driven by CLK/CYC body-specific sites reduced the reporter expression in abdomens [142]. A recent study identified additional motifs and transcription factors, which drive tissue-specific circadian gene expression [125]. However, in this study, only 20% of cycling genes were shown to contain CLK/CYC binding sites [125].…”

Section: Tissue-specific Rhythmic Gene Expressionmentioning

confidence: 55%

“…These reactions are catalyzed by a group of enzymes encoded by 'Halloween genes' including phantom, disembodied, shadow, and shade, involved in the terminal hydroxylation steps (reviewed in [122]). Ecdysteroidogenic genes do not exhibit high amplitude oscillations in transcript levels in head extracts [123,124] or in other peripheral tissues [125], suggesting that regulation of ecdysteroid biosynthesis occurs in posttranscriptional level. The source of cycling 20E in the head is not clear, however, downregulation of phantom in clock neurons (LNvs) reduces the behavioral rhythmicity and slightly lengthens the circadian period [119], therefore, pacemaker neurons might be involved in the biosynthesis of 20E.…”

Section: A Potential Systemic Entrainment Cue: Ecdysonementioning

confidence: 97%

“…Over 40% and 80% of protein coding genes in mice [138] and in baboons [139], respectively, are rhythmically expressed across different tissues. In flies, a recent study identified ~1700 cycling genes in four major tissues: brain, gut, MT, and fat body [125]. Even though a significant portion of the genome exhibits temporal expression patterns in at least one tissue, there is very little overlap of cycling genes, besides central clock genes, among different tissues [140,141].…”

Section: Tissue-specific Rhythmic Gene Expressionmentioning

confidence: 99%

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Roles of peripheral clocks: lessons from the fly

Yildirim¹,

Curtis

Hwangbo

2021

FEBS Letters

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To adapt to and anticipate rhythmic changes in the environment such as daily light-dark and temperature cycles, internal timekeeping mechanisms called biological clocks evolved in a diverse set of organisms, from unicellular bacteria to humans. These biological clocks play critical roles in organisms' fitness and survival by temporally aligning physiological and behavioral processes to the external cues. The central clock is located in a small subset of neurons in the brain and drives daily activity rhythms, whereas most peripheral tissues harbor their own clock systems, which generate metabolic and physiological rhythms. Since the discovery of Drosophila melanogaster clock mutants in the early 1970s, the fruit fly has become an extensively studied model organism to investigate the mechanism and functions of circadian clocks. In this review, we primarily focus on D. melanogaster to survey key discoveries and progresses made over the past two decades in our understanding of peripheral clocks. We discuss physiological roles and molecular mechanisms of peripheral clocks in several different peripheral tissues of the fly.

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Extensive tissue-specific expression variation and novel regulators underlying circadian behavior

Cited by 26 publications

References 97 publications

Central and Peripheral Clock Control of Circadian Feeding Rhythms

Central and Peripheral Clock Control of Circadian Feeding Rhythms

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

Roles of peripheral clocks: lessons from the fly

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