Identification of functional clock-controlled elements involved in differential timing of Per1 and Per2 transcription

Yamajuku, Daisuke; Shibata, Yasutaka; Kitazawa, Masashi; Katakura, Toshie; Urata, Hiromi; Kojima, Tomoko; Nakata, Osamu; Hashimoto, Seiichi

doi:10.1093/nar/gkq678

Cited by 27 publications

(25 citation statements)

References 40 publications

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“…After stimulation with DEX, all the reporter constructs displayed circadian oscillation patterns; however, this induction was not observed in GRE mut or E2 mut (Supplementary Figure S6A). The mutant reporters exhibited a slightly advanced phase compared with the WT reporter, as previously described (Supplementary Figure S6B) (36,37). Using these constructs, we generated adenoviruses expressing the PER2::LUC fusion protein (PER2 REC) driven by WT or mutant promoters (GRE mut and E2 mut ).…”

Section: Resultssupporting

confidence: 78%

“…The oscillation-driving region contains a non-canonical E-box (E1), which is an essential and sufficient element for the generation of rhythm, whereas the phase-delaying region contains GE2 (56). Yamajuku et al (37) demonstrated similar results in that the region from −161 to −143, which contains E2, was shown to be responsible for the phase delay. Although they used different stimuli (i.e.…”

Section: Discussionmentioning

confidence: 72%

“…This region includes a non-canonical E-box (E1) that is sufficient for self-sustained circadian rhythm generation and a D-box that is implicated in higher amplitude generation (37,56). In addition, we found that GE2 in this region is also conserved in mammals, but only 5 bp (CATGG) in the middle of the GRE sequence is conserved in zebrafish (58).…”

Section: Discussionmentioning

confidence: 99%

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Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

Cheon

Park

Cho

et al. 2013

Nucleic Acids Research

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Glucocorticoid (GC) signaling synchronizes the circadian rhythm of individual peripheral cells and induces the expression of circadian genes, including Period1 (Per1) and Period2 (Per2). However, no GC response element (GRE) has been reported in the Per2 promoter region. Here we report the molecular mechanisms of Per2 induction by GC signaling and its relevance to the regulation of circadian timing. We found that GC prominently induced Per2 expression and delayed the circadian phase. The overlapping GRE and E-box (GE2) region in the proximal Per2 promoter was responsible for GC-mediated Per2 induction. The GRE in the Per2 promoter was unique in that brain and muscle ARNT-like protein-1 (BMAL1) was essential for GC-induced Per2 expression, whereas other GRE-containing promoters, such as Per1 and mouse mammary tumor virus, responded to dexamethasone in the absence of BMAL1. This specialized regulatory mechanism was mediated by BMAL1-dependent binding of the GC receptor to GRE in Per2 promoter. When Per2 induction was abrogated by the mutation of the GRE or E-box, the circadian oscillation phase failed to be delayed compared with that of the wild-type. Therefore, the current study demonstrates that the rapid Per2 induction mediated by GC is crucial for delaying the circadian rhythm.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

Cheon

Park

Cho

et al. 2013

Nucleic Acids Research

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“…The significance of the positive regulation was verified further by the fact that the Per2::luc reporter gene that could not be transactivated by PER1/2 ( delta-Per2::luc ) lost the phase delay observed in wild-type Per2::luc . A recent report indicated that E*-box in Per2 promoter contributes to 1.5-hour phase delay of Per2 expression [33], and this might cause a residual 1-hour delay detected in delta-Per2::luc . However, the residual delay was not statistically significant (Student's t-test, n = 3, P>0.05).…”

Section: Discussionmentioning

confidence: 99%

Positive Autoregulation Delays the Expression Phase of Mammalian Clock Gene Per2

et al. 2011

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In mammals, cellular circadian rhythms are generated by a transcriptional-translational autoregulatory network that consists of clock genes that encode transcriptional regulators. Of these clock genes, Period1 (Per1) and Period2 (Per2) are essential for sustainable circadian rhythmicity and photic entrainment. Intriguingly, Per1 and Per2 mRNAs exhibit circadian oscillations with a 4-hour phase difference, but they are similarly transactivated by CLOCK-BMAL1. In this study, we investigated the mechanism underlying the phase difference between Per1 and Per2 through a combination of mathematical simulations and molecular experiments. Mathematical analyses of a model for the mammalian circadian oscillator demonstrated that the slow synthesis and fast degradation of mRNA tend to advance the oscillation phase of mRNA expression. However, the phase difference between Per1 and Per2 was not reproduced by the model, which implemented a 1.1-fold difference in degradation rates and a 3-fold difference in CLOCK-BMAL1 mediated inductions of Per1 and Per2 as estimated in cultured mammalian cells. Thus, we hypothesized the existence of a novel transcriptional activation of Per2 by PER1/2 such that the Per2 oscillation phase was delayed. Indeed, only the Per2 promoter, but not Per1, was strongly induced by both PER1 and PER2 in the presence of CLOCK-BMAL1 in a luciferase reporter assay. Moreover, a 3-hour advance was observed in the transcriptional oscillation of the delta-Per2 reporter gene lacking cis-elements required for the induction by PER1/2. These results indicate that the Per2 positive feedback regulation is a significant factor responsible for generating the phase difference between Per1 and Per2 gene expression.

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“…Luciferase activity was chronologically monitored at 37°C in 5% CO 2-95% air with a Kronos Dio AB-2550 luminometer (ATTO, Tokyo, Japan) interfaced to a computer for continuous data acquisition, as described (20,24). Bioluminescence records were detrended from the raw data (57). The cycle time and amplitude were calculated from the first to the third peaks of oscillations.…”

Section: Animalsmentioning

confidence: 99%

Contribution of FSH and triiodothyronine to the development of circadian clocks during granulosa cell maturation

Chu

Misawa

Chen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The involvement of FSH and triiodothyronine (T 3) in circadian clocks was investigated using immature granulosa cells of ovaries during the progress of cell maturation. Granulosa cells were prepared from preantral follicles of mouse Period2 (Per2)-dLuc reporter gene transgenic rats injected subcutaneously with the synthetic nonsteroidal estrogen diethylstilbestrol. Analysis of the cellular clock of the immature granulosa cells was performed partly using a serum-free culture system. Several bioluminescence oscillations of Per2-dLuc promoter activity were generated in the presence of FSH ϩ fetal bovine serum, but not in the presence of either FSH or serum. As revealed by bioluminescence recording and analysis of clock gene expression, the granulosa cells lack the functional cellular clock at the immature stage, although Lhr was greatly expressed during the period of cell maturation. The granulosa cells gained a strong circadian rhythm of bioluminescence during stimulation with FSH, whereas LH reset the cellular clock of matured granulosa cells. During strong circadian rhythms of clock genes, the Star gene showed significant expression in matured granulosa cells. In contrast, T 3 showed an inhibitory effect on the development of the functional cellular clock during the period of cell maturation. These results indicate that FSH provides a cue for the development of the functional cellular clock of the immature granulosa cells, and T3 blocks the development of the cellular clock.follicle-stimulating hormone; granulosa cells; clock genes; cell maturation IN MAMMALS, OVARIAN FOLLICLES MANIFEST in different stages of development: the primordial, primary, secondary, secondaryvesicular, and mature stages. FSH and LH influence immature and mature granulosa cells, respectively, and this influence promotes proliferation and maturation of the follicular cells and the synthesis of sex steroid hormones. The cellular clock may contribute to the progress of ovarian growth, via fluctuating hormones. This contribution by the cellular clock may be due to the finding that the clock genes, such as Period1-2 (Per1-2), are differently expressed in ovarian cells (21,36). The Per2 gene may be regulated by various hormones in particular, because many regulatory elements are located in the 5= flanking region of the Per2 promoter, including steroid hormone response element-half sites and the cAMP response element, as well as E-box and D-box elements.The clock system generates circadian changes in cellular functions via identified transcriptional and posttranscriptional regulatory processes. The cellular clock components CLOCK and BMAL1 bind to the E-box enhancer and positively drive expression of the Per genes and the Cryptochrome genes (Cry1-2) (45, 53). Further adding to the complexity, CLOCK-BMAL1 heterodimers induce expression of a nuclear orphan receptor, Rev-erb␣, resulting in the repression of the transcription of Bmal1 through direct binding to the Rev-erb␣ response element (RRE), located in the Bmal1 promoter (3, 11). The phosphoryl...

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Identification of functional clock-controlled elements involved in differential timing of Per1 and Per2 transcription

Cited by 27 publications

References 40 publications

Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

Positive Autoregulation Delays the Expression Phase of Mammalian Clock Gene Per2

Contribution of FSH and triiodothyronine to the development of circadian clocks during granulosa cell maturation

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