Figure 1.

MiRNA regulation of core clock components. A schematic of a molecular circadian system composed of core clock genes is shown. The transcription factors CLOCK:BMAL1 bind to target E-Box and activate the clock genes Per, Cry, Dbp, Rev-erb and Ror, as well as clock-controlled genes, including miRNAs. After PER and CRY are synthesized in the cytoplasm, these proteins form a complex and inhibit CLOCK:BMAL1-mediated transactivation. PER proteins are phosphorylated by CKIε and/or GSK-3β and dephosphorylated by PPP1 in order to regulate the cellular distribution and/or stability. In turn, RORα activates whereas Rev-erbα reduces the transcription of Cry, Bmal1 and miRNAs and other output genes that have RORE in the region upstream of the promoter. The DBP-dependent transactivation is repressed by competitive binding of E4BP4 to the D-box. Several miRNAs directly down-regulate these core clock components and modulate circadian rhythm.