Figure 6. Model of TFEB/TFE3 regulation of the oscillation of gene expression.

In the absence of nutrients (light phase), TFEB and TFE3 translocate to the nucleus and regulate the expression of genes involved in autophagy and metabolism by binding their promoter at E‐Boxes/CLEAR sites. On the other hand, TFEB and TFE3 regulate the expression of REV‐ERBα that binds ROREs in the promoter of its target genes, including TFEB/TFE3 target genes. Since REV‐ERBα displays a robust oscillation of its protein levels peaking at around ZT8, the repression of autophagy by REV‐ERBα results in a strong day–night transition. This temporal balance of autophagy stimulation (due to TFEB and TFE3 activation) and inhibition (due to the repressor REV‐ERBα) results in its circadian oscillation.