Many physiological processes exhibit circadian rhythms driven by cellular clocks composed of interlinked activating and repressing elements. To investigate temporal regulation in this molecular oscillator, we combined mouse genetic approaches and analyses of interactions of key circadian proteins with each other and with clock gene promoters. We show that transcriptional activators control BRD4-PTEFb recruitment to E-box-containing circadian promoters. During the activating phase of the circadian cycle, the lysine acetyltransferase TIP60 acetylates the transcriptional activator BMAL1 leading to recruitment of BRD4 and the pause release factor P-TEFb, followed by productive elongation of circadian transcripts. We propose that the control of BRD4-P-TEFb recruitment is a novel temporal checkpoint in the circadian clock cycle.
- Henrik Oster
- Gregor Eichele
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Mouse handling was carried out in accordance with the German Law on Animal Welfare and was ethically approved and licensed by the Office of Consumer Protection and Food Safety of the State of Lower Saxony (license numbers 33.11.42502-04/072/07 and 33.9-42502-04-12/0719).
- Asifa Akhtar, Max Planck Institute for Immunobiology and Epigenetics, Germany
- Received: November 1, 2018
- Accepted: July 10, 2019
- Accepted Manuscript published: July 11, 2019 (version 1)
© 2019, Petkau et al.
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