Acetylation of BMAL1 by TIP60 controls BRD4-P-TEFb recruitment to circadian promoters.

Nikolai Petkau,Gregor Eichele,Xunlei Zhou,Henrik Oster,Harun Budak

doi:10.7554/elife.43235

Nikolai Petkau, Gregor Eichele + Show 3 more

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https://doi.org/10.7554/elife.43235

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Journal: eLife	Publication Date: Jul 11, 2019
Citations: 26	License type: CC BY 4.0

Affiliation: Max Planck Institute for Biophysical Chemistry

Abstract

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.

Highlights

Circadian clocks are genetically encoded, self-sustained molecular oscillators that drive biological rhythms with a period close to 24 hr (Partch et al, 2014)
Treatment of fibroblasts with FP strongly reduced endogenous mRNA expression levels of Dbp (D-site albumin promoter binding protein), Per1, and Nr1d1 (Figure 1—figure supplement 1C) that are direct CLOCK-BMAL1 targets (Stratmann et al, 2012). These findings suggest that circadian clock gene regulation occurs at the initiation of transcription (Le Martelot et al, 2012) and at the level of polymerase II (Pol II) pause release and productive elongation
Genome-wide Chromatin immunoprecipitation (ChIP) studies (Koike et al, 2012; Menet et al, 2012; Rey et al, 2011) show that at the onset of the circadian cycle, the circadian repressor protein CRY1 is associated with chromatinbound CLOCK-BMAL1 located near Pol II

Summary

Introduction

Circadian clocks are genetically encoded, self-sustained molecular oscillators that drive biological rhythms with a period close to 24 hr (Partch et al, 2014) They are found in most organisms and even in cultured tissues and cells (Balsalobre et al, 1998; Brown et al, 2012; Yoo et al, 2004). In mammals, these clocks are organized in a network controlled by a master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) (Dibner et al, 2010). Positive components are the heterodimers of CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle ARNT-like protein 1) that bind to E-box promoter elements of Per (Period), Cry1/2 (Cryptochome) and Rev-ErbAa/b (Nr1d1/2; nuclear receptor subfamily 1, group D, members 1 and 2) that encode repressor proteins PER, CRY and NR1D (Takahashi, 2017)

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