TFEB regulates PER3 expression via glucose-dependent effects on CLOCK/BMAL1

It has been reported that metabolites regulate circadian rhythms through direct effects on clock genes. A metabolic network involving PER3 raises the possibility that some metabolic regulators are directly involved in the mammalian clock. Here, we show that the bHLH family transcription factor TFEB regulates PER3 through the CLOCK/BMAL1 complex. In the liver, TFEB expression displays circadian rhythms. A loss of TFEB function disrupts and dampens the expression of PER3 but not the expression of other circadian genes, such as PER1, PER2, CRY1 and CRY2. TFEB physically interacts with CLOCK/BMAL1 through its N-terminal region. In the presence of TFEB, BMAL1/CLOCK-mediated transcription is enhanced. Moreover, the TFEB/CLOCK/BMAL1 complex is regulated by glucose. These results show that TFEB has a role in the mammalian clock mechanism.