The BMAL1 C terminus regulates the circadian transcription feedback loop

Kiyohara, Yota B.; Tagao, Sayaka; Tamanini, Filippo; Morita, Akira; Sugisawa, Yukiko; Yasuda, Maya; Yamanaka, Iori; Ueda, Hiroki R.; Horst, Gijsbertus T. J. van der; Kondo, Takao; Yagita, Kazuhiro

doi:10.1073/pnas.0601416103

Cited by 103 publications

(142 citation statements)

References 28 publications

(34 reference statements)

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“…1D), substantially weakened the BiFC between BMAL1 and CBP, whereas overexpression of CLOCK strengthened the signal (Y.L., unpublished data). Intriguingly, the BMAL1 C-terminal domain was found to also associate with CRY1, a potent repressor of the CLOCK-BMAL1 heterodimer, thereby suppressing its target gene transcription (Kiyohara et al, 2006;Sato et al, 2006). These findings present the possibility that the BMAL1 C-terminal has antagonistic dual functions and serves as a molecular switch for the gene transcription controlled by the CLOCK-BMAL1 heterodimer.…”

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confidence: 74%

Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Lee

Kwon

et al. 2010

Journal of Cell Science

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SummaryThe transcription factor CLOCK-BMAL1 is a core component of the molecular clock machinery that drives circadian gene expression and physiology in mammals. Recently, we reported that this heterodimeric transcription factor functions as a signaling molecule in response to the resetting stimuli via the Ca 2+ -dependent protein kinase C pathway. Here, we demonstrate that the CREB-binding protein (CBP) plays a key role in rapid activation of the CLOCK-BMAL1 heterodimer that leads to phase resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation (BiFC) assay revealed that CLOCK and BMAL1 dimerize in the cytoplasm and subsequently translocate into the nucleus in response to serum stimuli (mean time duration was 29.2 minutes and mean velocity 0.7 m/minute). Concomitantly, BMAL1 rapidly recruited CBP on Per1 promoter E-box, but not p300 (a functional analog of CBP), in the discrete nuclear foci. However, recruitment of CBP by cAMP/Ca 2+ response element-binding (CREB) protein on CRE was not markedly increased upon delivery of the resetting stimuli. Furthermore, overexpression of CBP greatly potentiated the CLOCK-BMAL1-mediated Per1 transcription, and this effect was completely abolished by site-directed mutation of E-box elements, but not by the mutation of CRE in the Per1 promoter. Furthermore, molecular knockdown of CBP severely dampened circadian oscillation of clock gene expression triggered by the resetting stimuli. These findings suggest that CBP recruitment by BMAL1 mediates acute transactivation of CLOCK-BMAL1, thereby inducing immediate-early Per1 transcription and phase resetting of the circadian clock.

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confidence: 74%

Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Lee

Kwon

et al. 2010

Journal of Cell Science

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“…Physical Interaction of PER2 with BMAL2 Is Stronger than That with BMAL1-PER2 is known to interact with BMAL1 (42,43), whereas the intimate functional linkage between PER2 and BMAL2 (Fig. 5) suggested that PER2 may associate with BMAL2 more efficiently than with BMAL1.…”

Section: Bmal2 Is Less Sensitive Than Bmal1 To Repression By Crys Butmentioning

confidence: 96%

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

Sasaki

Yoshitane

et al. 2009

Journal of Biological Chemistry

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In the molecular oscillatory mechanism governing circadian rhythms, positive regulators, including CLOCK and BMAL1, transactivate Per and Cry genes through E-box elements, and translated PER and CRY proteins negatively regulate their own transactivation. Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription, but the role of BMAL2 in the circadian clockwork is still elusive. Here we characterized BMAL2 function in NIH3T3 cells and found that the cellular rhythms monitored by Bmal1 promoterdriven bioluminescence signals were blunted by RNA interference-mediated suppression of Bmal2 as well as that of Bmal1. Transcription assays with a 2.1-kb mPer1 promoter revealed that CRY2 inhibited the transactivation mediated by BMAL1-CLOCK more strongly than that by BMAL2-CLOCK. In contrast, PER2 showed a stronger inhibitory effect on BMAL2-CLOCK than on BMAL1-CLOCK. The molecular link between BMAL2 and PER2 was further strengthened by the fact that PER2 exhibited a greater affinity for BMAL2 than for BMAL1 in co-immunoprecipitation experiments. These results indicate a functional partnership between BMAL2 and PER2 and reemphasize the negative role of PER2 in the circadian transcription. As a broad spectrum function, BMAL2-CLOCK activated transcription from a variety of SV40-driven reporters harboring various E/E-box-containing sequences present in the upstream regions of clock and clock-controlled genes. Importantly, the efficiencies of BMAL2-CLOCK-mediated transactivation relative to that achieved by BMAL1-CLOCK were dependent heavily on the E-box-containing sequences, supporting distinguishable roles of the two BMALs. Collectively, it is strongly suggested that BMAL2 plays an active role in the circadian transcription.A variety of organisms from bacteria to humans show circadian rhythms in physiology and behavior under the regulation of endogenous circadian clocks oscillating with an ϳ24-h periodicity (1, 2). In mammals, the central clock is located in the hypothalamic suprachiasmatic nucleus, whereas peripheral clocks with self-sustainable oscillation machinery are located in many peripheral tissues (3). Even cultured fibroblasts were shown to retain the cellular clocks (4), and hence they have been used for studies on the oscillatory mechanism of peripheral clocks. The molecular clockwork in mammals centers on transcription/translation-based autoregulatory feedback loops of clock genes, to which bHLH 3 -PAS proteins, BMAL1 and CLOCK, contribute as positive regulators of the transcription (2, 5). BMAL1-CLOCK complex activates transcription through CACGTG-type E-box and its related sequences found in promoter regions of clock genes and clock-controlled genes such as Per1 (6), Per2 (CACGTT E-box-like or EЈ-box sequence; see Ref. 7), plasminogen activator inhibitor-1 (PAI-1) (8), and Rev-Erb␣/␤ (9, 10). The E-box-dependent transactivation mediated by the BMAL1-CLOCK complex is suppressed by an expanding number of negative regulators, including PER1 (11, 12), PER2 (13-15), PER3 (16,1...

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“…5 A and B). The BMAL1-DN, which lacks the Cterminal region of BMAL1 protein, strongly suppresses the BMAL1/CLOCK-mediated transcription (28). To confirm the effect of BMAL1-DN on the endogenous clock genes in somatic cells, we analyzed the expression levels of endogenous clock genes before and after the expression of BMAL1-DN in NIH 3T3 cells.…”

Section: Expression Of Clock Genes In Es Cells Ips Cells and Differmentioning

confidence: 99%

Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro

Yagita

Horie²,

Koinuma³

et al. 2010

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

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The molecular oscillations underlying the generation of circadian rhythmicity in mammals develop gradually during ontogenesis. However, the developmental process of mammalian cellular circadian oscillator formation remains unknown. In differentiated somatic cells, the transcriptional-translational feedback loops (TTFL) consisting of clock genes elicit the molecular circadian oscillation. Using a bioluminescence imaging system to monitor clock gene expression, we show here that the circadian bioluminescence rhythm is not detected in the mouse embryonic stem (ES) cells, and that the ES cells likely lack TTFL regulation for clock gene expression. The circadian clock oscillation was induced during the differentiation culture of mouse ES cells without maternal factors. In addition, reprogramming of the differentiated cells by expression of Sox2, Klf4, Oct3/4, and c-Myc genes, which were factors to generate induced pluripotent stem (iPS) cells, resulted in the re-disappearance of circadian oscillation. These results demonstrate that an intrinsic program controls the formation of the circadian oscillator during the differentiation process of ES cells in vitro. The cellular differentiation and reprogramming system using cultured ES cells allows us to observe the circadian clock formation process and may help design new strategies to understand the key mechanisms responsible for the organization of the molecular oscillator in mammals.circadian clock | induced pluripotent stem cells | real-time monitor T he circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as the sleep-wake cycle, energy metabolism, and the endocrine system (1, 2). These physiological rhythms develop gradually in the first year of life in humans (3). It is well known that the human sleep-wake rhythm is generated within a few months after birth. However, a weak circadian rhythm of core body temperature is present immediately after birth, suggesting that the development of the human circadian rhythms starts during fetal life. In fact, recent studies in rodents have suggested the appearance of circadian molecular rhythms in the suprachiasmatic nucleus (SCN) a few days before birth (4). However, little information is available on the development of the mammalian cellular circadian oscillator.In mammals, molecular oscillation of the circadian clock consists of interlocked positive and negative transcription/translation feedback loops (TTFL) involving a set of clock genes and clock-controlled output genes that link the oscillator to the clock-controlled processes (5). CLOCK and BMAL1 are basic-helix-loop-helix (bHLH) PAS transcription factors that heterodimerize and transactivate the core clock genes such as Period (Per1, -2, and -3), Cryptochrome (Cry1 and Cry2), and Rev-Erbα (2, 5, 6). PER and CRY proteins suppress the activity of the CLOCK/BMAL1, whereas REV-ERBα suppresses Bmal1 gene expression.In this study, we focused on the development of the mammalian circadian oscillator du...

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The BMAL1 C terminus regulates the circadian transcription feedback loop

Cited by 103 publications

References 28 publications

Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro

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