title: A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery.
abstract: Circadian clocks in mammals are built on a negative feedback loop in which the heterodimeric transcription factor circadian locomotor output cycles kaput (CLOCK)-brain, muscle Arnt-like 1 (BMAL1) drives the expression of its own inhibitors, the PERIOD and CRYPTOCHROME proteins. Reactivation of CLOCK-BMAL1 occurs at a specific time several hours after PERIOD and CRYPTOCHROME protein turnover, 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 selective coactivator for CLOCK-BMAL1, which oscillates under CLOCK-BMAL1 transcriptional control. TRAP150 promotes CLOCK-BMAL1 binding to target genes and links CLOCK-BMAL1 to the transcriptional machinery at target-gene promoters. Depletion of TRAP150 caused low-amplitude, long-period rhythms, identifying it as a positive clock element. The activity of TRAP150 defines a positive feedback loop within the clock and provides a potential mechanism for timing the reactivation of circadian transcription.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Laura
authors.initials: L
authors.lastname: Lande-Diner
authors.forename: Cyril
authors.initials: C
authors.lastname: Boyault
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Weitz
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; D004268:DNA-Binding Proteins; C475774:THRAP3 protein, human; D014157:Transcription Factors; D056926:CLOCK Proteins
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