The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks
© Nakahata et al; licensee BioMed Central Ltd. 2006
Received: 23 September 2005
Accepted: 16 February 2006
Published: 16 February 2006
Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN) of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure.
We developed the in vitro real-time oscillation monitoring system (IV-ROMS) by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid) have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ), triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Rorα mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-γ – and MAPKs (ERK, JNK, p38MAPK)-independent.
Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight novel and four known molecules to be potential entrainment factors for circadian clocks, indicating that this assay system is a powerful and useful tool in initial screenings.
Circadian rhythms are endogenous self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes [1, 2] In mammals the circadian orchestration of these processes is governed by pacemaker cells located within the suprachiasmatic nuclei (SCN) of the hypothalamus. It has also revealed that in mammals circadian oscillators exist not only in the SCN but also in peripheral tissues, and even in immortalized cells [3–5]. Because the periodicity of the circadian clock only approximates that of the environment, circadian clocks have to be adjusted to 24-h/day period by environmental time cues . Circadian clocks are primarily synchronized with environmental time by the daylight cycle as an input signal to the SCN through the direct and indirect neural projections from retinal ganglion cells [6, 7], however, other non-photic cues can also synchronize circadian clocks to 24-h/day .
The molecular mechanism of the circadian oscillator as a transcriptional-translational feedback loop has been unraveled by genetic analysis in Drosophila and mammals [8, 9]. These molecular mechanisms based on the transcriptional-translational regulation are conserved among many species, including Arabidopsis, Neurospora, Drosophila, zebrafish, and mammals [9–11]. In mammals, principally two basic helix-loop-helix-PAS transcriptional factors, CLOCK and BMAL1, regulate gene expression by interacting with a promoter element termed E-box [12, 13]. Target genes of these transcriptional factors include several repressor proteins, including PER1, PER2, PER3, CRY1, and CRY2, which function to inhibit the activity of CLOCK/BMAL1 complex by entering into the nucleus [14, 15], thereby generating a circadian oscillation of their own transcription.
One of the molecular features of circadian clocks is rhythmic fluctuation of clock gene mRNA amounts. In situ hybridization and RNase protection assay are conventional techniques used to detect expression profiles of the clock and clock-controlled genes (for example, [4, 16, 17]). Quantitative real-time RT-PCR has recently become a popular method to investigate mRNA expression profiles (for example, [5, 18]). The bioluminescent firefly luciferase protein has proven to be a useful reporter protein for monitoring the dynamics of gene activity in living cells . Luminescence from luciferase expressed in transgenic plants, Drosophila, zebrafish and mammals has been used to monitor real-time dynamic change in gene transcription within the living organism [19–22]. Since this system is applied to transiently transfected cell cultures with clock gene promoters driving firefly luciferase gene expression [5, 23], luciferase real-time monitoring system using photomultiplier tubes has become a powerful tool to investigate circadian clock mechanism, in particular to identify the critical elements for producing the circadian rhythmicity [24–26].
As described above, it has been thought that circadian clocks in peripheral tissues are regulated by the SCN via the secretion of hormones and/or the sympathetic/parasympathetic innervations from the SCN to peripheral tissues . Recently, some potential "entrainment factors" have been reported [28–32], however, the mechanisms how the central SCN pacemaker clock orchestrates the peripheral clocks remains unclear. Here, we report systematic screening of various molecules in attempt to find entrainment factors by using our in vitro real-time oscillation monitoring system (IV-ROMS). In this study, we report eight novel candidates, including 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), of entrainment factors for circadian clocks.
Results and discussion
Establishment of IV-ROMS using mPer2-luc/Rat1 cell lines
Screening of peptide and bioactive lipid libraries for circadian entrainment factors
The results of screening are shown in Figure 1B and Additional file 2 by using Peptide library (BAP96S, assayscript, Osaka, Japan) and Bioactive lipid library (Version 3, BIOMOL, PA, USA). Out of 299 compounds screened, 12 demonstrated the rhythmic expression of luciferase. Among them, four compounds (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid) have already been reported as resetting factors in vivo or in vitro [30, 34]. By this assay, we newly identified eight candidates for circadian entrainment factors; prostaglandin J2 (PGJ2), Δ12-PGJ2, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), enantio-PAF C16, 1-acyl-PAF, 6-formylindolo [3,2-B] carbazole, palmitoyl dopamine, and arachidonoyl dopamine. These two libraries contain five known entrainment factors and we could identify all of them, except prostaglandin E2 , as an entrainment factor by this assay system (see Additional file 2), indicating that this assay system is reliable and suitable for screening of entrainment factors. We could not identify prostaglandin E2 because prostaglandin E2 receptor EP1, which is responsible for the entrainment of circadian clocks, was not expressed in Rat1 cells, but was expressed in NIH3T3 cells that Tsuchiya et al used  (see Additional file 3).
15d-PGJ2 triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells
15d-PGJ2 up-regulates Cry1, Cry2, and Rorα mRNA expressions
Entrainment triggered by 15d-PGJ2 is independent of PPAR-γ signaling pathway
We then explored which signaling pathways are involved in 15d-PGJ2-induced rhythmic clock gene expression. Recently, administration of 15d-PGJ2 was shown to activate ERK and JNK signaling pathways [42, 46]. The known entrainment factors are thought to mainly act by activating ERK signaling pathway . We thus examined whether these two MAPK signaling pathways can be linked with 15d-PGJ2-induced cyclic gene expression. Surprisingly, pretreatment of a specific JNK inhibitor SP600125  and of a specific MEK inhibitor U0126 , both showed no effect on the entrainment of circadian clocks (Fig. 4). Although results of MAPK/ERK to entrainment in the different systems have been inconsistent , these results suggest that there exists an unknown entrainment pathway, independent of the ERK-mediated signaling pathway. Meanwhile, another pathway, the p38 MAPK signaling pathway was recently shown to be associated with circadian clocks by modulating their period lengths . SB203580, a specific p38 inhibitor , slightly delayed the phase of Per2 rhythms but did not affect circadian expression of both Per2 and Bmal1 (Fig. 4), indicating that p38 MAPK signaling pathway is involved in modulation of period length, but not in the induction of clock gene expression by 15d-PGJ2.
In vitro real-time oscillation monitoring system (IV-ROMS)
IV-ROMS can be applied to identify molecules which are involved in other mechanisms pertaining to circadian clock system; transcriptional-translational feedback loops of circadian mechanism and input signaling pathway mechanism, for example, by using RNAi, inhibitor, and other libraries. We can also apply this system to other research fields. Further modification and development of this system will be needed in order to be applied for more systematic and high-throughput screenings.
Here we present the in vitro real-time oscillation monitoring system (IV-ROMS). Indeed, we newly found eight candidates out of 299 compounds as circadian entrainment factors (Fig. 1 and Additional file 2). We further confirmed that one of the candidates, 15d-PGJ2, triggers the rhythmic expression of endogenous circadian clocks by inducing Cry s and Rorα, but not Per s, in NIH3T3 cells (Fig. 2), indicating that this assay system is a powerful and useful tool for the initial screening procedure. This system can also be applied not only to find new intracellular molecules involved in circadian clocks; new transcription factors, new signaling and degradation pathways, but also to investigate other cellular mechanisms like cell-cycle or oncogenesis.
Rat1 and NIH3T3 fibroblast cells were grown at 37°C and 5% CO2. Rat1 and NIH3T3 cells were grown in Dulbecco's Modified Eagle Medium (1.0 g/L glucose) with L-Gln and sodium pyruvate (DMEM, Nacalai tesque, Kyoto, Japan) supplemented with 5 and 10% fetal bovine serum (FBS), respectively, and antibiotics.
Establishment of mPer2-luciferase-stably-expressing Rat1 cell line
A bacterial artificial chromosome (BAC) clone (pBeloBac11 24484) containing the complete genomic sequence of the mouse Per2 (mPer2) gene was purchased from BACPAC Resource Center at Children's Hospital Oakland Research Institute. The mPer2 promoter region was isolated and cloned in the pGL3 Basic vector (Promega). The mPer2 region spans from -2811 to +110 (+1 indicates the putative transcriptional start site). Rat1 cells were cotransfected with linearized mPer2 promoter/pGL3 and pcDNA3, which contains neomycin resistant gene. Transfection was carried out by using Polyfect Transfection Reagent (QIAGEN) according to the manufacture's instructions. The cells were cultured in 10% FBS/DMEM containing 500 μg/ml geneticin (SIGMA) for 1 to 2 weeks. Cells were then individually isolated, and 24 clones were established as mPer2-luc/Rat1 cells. After screening for the luciferase activity by using IV-ROMS, we established two independent clones with clear rhythmic activity.
Real-time luciferase activity monitoring in living cells
mPer2-luc/Rat1 cells were seeded in a 35 mm-dish at density of 2 × 105 cells and incubated for 2 days. The medium was then exchanged for serum-free medium supplemented with a compound to be screened. Compound was diluted to a final concentration of 1 μM for peptide and 1 or 10 μM for bioactive lipid, respectively. One hour later the medium was replaced with 1% FBS/DMEM supplemented with 0.1 mM luciferin/10 mM HEPES (pH 7.2). Light emission was measured and integrated for 1 min at intervals of 15 min with a photomultiplier tube (Hamamatsu Photonics, Hamamatsu, Japan). Data were analyzed by LM2400 software (Hamamatsu Photonics).
Real-time quantitative RT-PCR
TaqMan® Low Density Array (Applied Biosystems), which contained mPer1, mPer2, mPer3, mArntl (mBmal1), mNpas2, mCry1, mCry2, mBhlhb2 (mDec1), mBhlhb3 (mDec2), mDbp, and mNfil3 (mE4bp4) as clock genes and 18S rRNA as an internal control, was examined by using an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) as described previously . For one port of the TaqMan Low Density Array, 100 ng cDNA template was mixed with 50 μl of 2 × TaqMan Universal PCR Master Mix (Applied Biosystems) and filled up to 100 μl with distilled water. The reaction was first incubated at 50°C for 2 min, then at 95°C for 10 min, followed by 40 cycles of 95°C for 15 sec and 60°C for 1 min.
Each real-time quantitative RT-PCR was performed by using an ABI PRISM 7900HT Sequence Detection System as described previously . Briefly, DNase-treated total RNA (1 μg) was reverse-transcribed by using a random hexamer primer and Superscript reverse transcriptase (Invitrogen). The cDNA equivalent to 50 ng total RNA was PCR-amplified. The PCR primers and TaqMan probes (5' FAM and 3' TAMRA) used are as follows:
mPer2 FW: CGC CTA GAA TCC CTC CTG AGA,
mPer2 RV: CCA CCG GCC TGT AGG ATC T,
mPer2 TaqMan probe: AGG CTG TGG ATG AAA GGG CGG TC,
mBmal1 FW: GCA GTG CCA CTG ACT ACC AAG A,
mBmal1 RV: TCC TGG ACA TTG CAT TGC AT,
mBmal1 TaqMan probe: ATC AAG AAT GCA AGG GAG GCC CAC A,
18S rRNA FW: CGC CGC TAG AGG TGA AAT TC,
18S rRNA RV: CGA ACC TCC GAC TTT CGT TCT,
18S rRNA TaqMan probe: CCG GCG CAA GAC GGA CCA GA.
The PCR primers for mCry1, mCry2, and mRorα were described previously [5, 24]. Values are reported as mean ± SE. Statistical differences were determined by a Student's t test. Statistical significance is displayed as * (p < 0.05) or ** (p < 0.01).
List of abbreviations used
in vitro real-time oscillation monitoring system
peroxisome proliferators-activated receptor-γ
reverse transcription-polymerase chain reaction
Dulbecco's modified eagle medium
Fetal bovine serum
We are grateful to Setsuko Tsuboi, Chiaki Matsubara, and Yoko Sakakida for their technical assistance. Also thank Yoshihiro Urade for discussion and Yasufumi Shigeyoshi for Rat1 cells. This work was supported in part by research grants from the MEXT and Takeda Science Foundation.
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