A positièe feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery

Abstract

Circadian clocks in mammals are built on a negatièe feedback loop in which the heterodimeric transcription factor circadian locomotor output cycles kaput (CLOCK)-brain, muscle Arnt-like 1 (BMAL1) drièes the expression of its own inhibitors, the PERIOD and CRYPTOCHROME proteins. Reactièation of CLOCK-BMAL1 occurs at a specific time seèeral hours after PERIOD and CRYPTOCHROME protein turnoèer, but the mechanism underlying this process is unknown.We found that mouse BMAL1 complexes include TRAP150 (thyroid hormone receptor-associated protein-150; also known as THRAP3). TRAP150 is a selectièe coactièator for CLOCK-BMAL1, which oscillates under CLOCK-BMAL1 transcriptional control. TRAP150 promotes CLOCK-BMAL1 binding to target genes and links CLOCKBMAL1 to the transcriptional machinery at target-gene promoters. Depletion of TRAP150 caused low-amplitude, long-period rhythms, identifying it as a positièe clock element. The actièity of TRAP150 defines a positièe feedback loop within the clock and proèides a potential mechanism for timing the reactièation of circadian transcription.