Nuclear Receptor-mediated Cell-autonomous Oscillatory Expression of the Circadian Transcription Factor, Neuronal PAS Domain Protein 2 (NPAS2)

作者：Matsumura Ritsuko; Matsubara Chiaki; Node Koichi; Takumi Toru^*; Akashi Makoto

来源：Journal of Biological Chemistry, 2013, 288(51): 36548-36553.

DOI：10.1074/jbc.M113.517235

• Circadian Clock
• Circadian Rhythms
• Clock Genes
• Nuclear Receptors
• Transcription
• Transcription Factors

Background: NPAS2 is a circadian transcription factor responsive to a wide range of intra- and extracellular stimuli. Results: Deficiency of ROR caused a damped transcriptional oscillation of Npas2 and functional depletion of an RORE resulted in a complete loss of the oscillation. Conclusion: Nuclear receptors elicit cell-autonomous circadian transcription of Npas2. Significance: Synchronous transcriptional oscillation of Npas2 with Bmal1 provides the foundation for efficient circadian input and robust oscillation. %26lt;br%26gt;NPAS2 (MOP4) is a heme-containing sensor transcription factor responsive to a wide range of intra- and extracellular stimuli, which also functions as a circadian transcription factor. This molecule forms a heterodimer with another circadian transcription factor, BMAL1, and activates transcription via E-box elements, indicating that circadian phase synchronization between NPAS2 and BMAL1 expression is important for the efficient transcriptional activation of target genes. However, details of the mechanism of cell-autonomous circadian transcription of Npas2 remain unclear. Here, we show that one of the ROREs (retinoid-related orphan receptor response elements) in the upstream region of the transcription start site is essential for circadian transcription of the Npas2 gene. Furthermore, we also show that endogenous ROR indeed plays an essential role in cell-autonomous circadian transcription of Npas2, because a damped transcriptional oscillation was observed not only by introduction of a dominant negative form or small interfering RNA but also in embryonic fibroblasts obtained from ROR-mutant (sg/sg) mice. These results indicate that circadian transcription of Npas2 is synchronized with that of Bmal1 in a cell-autonomous nuclear receptor-mediated fashion.

• 出版日期2013-12-20