<i>Drosophila</i> CLOCK target gene characterization: implications for circadian tissue-specific gene expression

Abruzzi, Katharine C.; Rodriguez, Joseph; Menet, Jérôme S.; Desrochers, Jennifer; Abigail, Zadina; Luo, Weifei; Tkachev, Sasha; Rosbash, Michael

doi:10.1101/gad.178079.111

Cited by 161 publications

(152 citation statements)

References 46 publications

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“…gol also was of interest because it is a direct target of the CLK-CYC complex and is an eye-specific gene. As perhaps should be expected, CLK binding to gol occurs only in eyes (8), emphasizing the tissue heterogeneity that underlies these head datasets. This heterogeneity makes it difficult to compare the head datasets with recent RNA-Seq data from dissected fly brains (35).…”

Section: Resultsmentioning

confidence: 92%

“…7). Nonetheless, many cycling mRNAs, including the core clock genes, continue to appear in different studies (8).…”

Section: Discussionmentioning

confidence: 99%

“…Cycling mRNAs are dependent on a functional pacemaker (6,7), but most probably are regulated only indirectly by the core circadian clock (8). In flies, this mechanism consists of the CLOCK and CYCLE heterodimer (CLK/CYC), which drives the rhythmic transcription of its repressor protein genes period and timeless (9).…”

Section: Nas-seq | Chromatin Dynamicsmentioning

confidence: 99%

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Nascent-Seq analysis of Drosophila cycling gene expression

Rodriguez

Tang

Khodor

et al. 2013

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

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100

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Rhythmic mRNA expression is a hallmark of circadian biology and has been described in numerous experimental systems including mammals. A small number of core clock gene mRNAs and a much larger number of output mRNAs are under circadian control. The rhythmic expression of core clock genes is regulated at the transcriptional level, and this regulation is important for the timekeeping mechanism. However, the relative contribution of transcriptional and posttranscriptional regulation to global circadian mRNA oscillations is unknown. To address this issue in Drosophila, we isolated nascent RNA from adult fly heads collected at different time points and subjected it to high-throughput sequencing. mRNA was isolated and sequenced in parallel. Some genes had cycling nascent RNAs with no cycling mRNA, caused, most likely, by light-mediated read-through transcription. Most genes with cycling mRNAs had significant nascent RNA cycling amplitudes, indicating a prominent role for circadian transcriptional regulation. However, a considerable fraction had higher mRNA amplitudes than nascent RNA amplitudes. The same comparison for core clock gene mRNAs gives rise to a qualitatively similar conclusion. The data therefore indicate a significant quantitative contribution of posttranscriptional regulation to mRNA cycling.Nas-seq | chromatin dynamics T he circadian clock controls the rhythmic expression of thousands of genes. These mRNAs mediate the oscillation of numerous biochemical, physiological, and behavioral functions. Although inconsistency among microarray datasets has made it difficult to identify a definitive set of mRNA cyclers in Drosophila, there is good agreement on a small number of robust cycling mRNAs (see below). Moreover, it appears that a much larger number of cycling mRNAs exist within circadian neurons (1), and thousands of mRNAs have been shown to oscillate within individual tissues in mammals (2-5).Cycling mRNAs are dependent on a functional pacemaker (6, 7), but most probably are regulated only indirectly by the core circadian clock (8). In flies, this mechanism consists of the CLOCK and CYCLE heterodimer (CLK/CYC), which drives the rhythmic transcription of its repressor protein genes period and timeless (9). After translation, the proteins PER and TIM decrease their own transcription by inhibiting the activity of CLK/ CYC (10-12). A set of largely orthologous proteins (CLK, BMAL1, PER, and CRYPTOCHROME) functions similarly in mammals. Although posttranslational regulation of these transcription factors makes a major contribution to core clock function (13-19), there is evidence that transcriptional regulation also is important for circadian timing. For example, flies with enhanced CLK/CYC-mediated transcription have unusually high levels of per mRNA and significantly shorter periods (20).The core clock model drives the assumption that the large population of cycling mRNAs-the hundreds or thousands of output mRNAs under circadian regulation-is also under transcriptional regulation. However, it is not known w...

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Section: Resultsmentioning

confidence: 92%

“…7). Nonetheless, many cycling mRNAs, including the core clock genes, continue to appear in different studies (8).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nascent-Seq analysis of Drosophila cycling gene expression

Rodriguez

Tang

Khodor

et al. 2013

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

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100

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“…Taken together, the results suggest that the behavioral phenotypes are caused not by the misregulation of circadian timekeeping but rather by the impact of altered TIM levels on the expression of numerous circadian output genes. This interpretation reflects the interaction of all four core clock transcription factors (CLK, CYC, PER, and TIM) with numerous output genes as well as with the core clock genes themselves (29,30).…”

Section: Discussionmentioning

confidence: 99%

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Xiao

Rosbash

2016

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

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Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light-dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir276a-binding site in the tim 3′ UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions. microRNA | circadian rhythms | light regulation | CRISPR

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“…Since bHLH transcription factors are known to bind to the consensus hexanucleotide sequence E-box (CANNTG) we focused on the various CLK-binding E-boxes described previously 39 . Twentyone E-boxes were found within a 12.5 kb region surrounding let-7-C. Sixteen of these E-boxes are evolutionarily conserved across five Drosophila genomes (D.melanogaster, D.simulans, D.sechellia, D.yakuba and D.erecta).…”

Section: =2498±004 H Pdf-gal4/+;uas-let-7/+mentioning

confidence: 99%

Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle

et al. 2014

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MicroRNA-mediated post-transcriptional regulations are increasingly recognized as important components of the circadian rhythm. Here we identify microRNA let-7, part of the Drosophila let-7-Complex, as a regulator of circadian rhythms mediated by a circadian regulatory cycle. Overexpression of let-7 in clock neurons lengthens circadian period and its deletion attenuates the morning activity peak as well as molecular oscillation. Let-7 regulates the circadian rhythm via repression of CLOCKWORK ORANGE (CWO). Conversely, upregulated cwo in cwo-expressing cells can rescue the phenotype of let-7-Complex overexpression. Moreover, circadian prothoracicotropic hormone (PTTH) and CLOCKregulated 20-OH ecdysteroid signalling contribute to the circadian expression of let-7 through the 20-OH ecdysteroid receptor. Thus, we find a regulatory cycle involving PTTH, a direct target of CLOCK, and PTTH-driven miRNA let-7.

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Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression

Cited by 161 publications

References 46 publications

Nascent-Seq analysis of Drosophila cycling gene expression

Nascent-Seq analysis of Drosophila cycling gene expression

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle

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