Abstract
The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period, Cryptochrome, and Rev-erb genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.
Highlights
The mammalian circadian clock network is programmed by a transcription–translation feedback loop comprised of basic helix–loop–helix activators (CLOCK/BMAL1) that induce the transcription of their own repressors (PERIOD [PER]/CRYPTOCHROME [CRY]/REV-ERBs) through binding to E-box elements within the promoters of these factors, thereby synchronizing behavioral and physiological rhythms in anticipation of the rising of the sun
The circadian clock is composed of transcriptional activators and repressors that generate periodic cycles of behavior and physiology that can be modulated in response to changes in the environment, including inflammation (Marpegan et al 2005; Okada et al 2008; Curtis et al 2015) and high-fat diet (HFD) in mice (Kohsaka et al 2007; Eckel-Mahan et al 2013)
We first treated wild-type mice with either saline or 20 mg/kg LPS (Spengler et al 2012; Curtis et al 2015) at Zeitgeber time 6 (ZT6) and performed chromatin immunoprecipitation and sequencing (ChIP-seq) of p65, CLOCK, BMAL1, acetylated H3K27 (H3K27ac), and total RNA polymerase II (Pol II) in the liver at ZT8, the zenith of NF-κB activity during acute infection and a peak time of BMAL1 binding in the liver (Fig. 1A; Rey et al 2011; Spengler et al 2012)
Summary
The mammalian circadian clock network is programmed by a transcription–translation feedback loop comprised of basic helix–loop–helix activators (CLOCK/BMAL1) that induce the transcription of their own repressors (PERIOD [PER]/CRYPTOCHROME [CRY]/REV-ERBs) through binding to E-box elements within the promoters of these factors, thereby synchronizing behavioral and physiological rhythms in anticipation of the rising of the sun This core clock cycle is amplified downstream through direct activation of genes containing a regulatory D-albuminbinding protein (DBP) motif, mediated by PAR-bZIP transcription factors (TFs; DBP, HLF, and TEF) and the E4BP4 repressor (NFIL3), which generate rhythmic physiological outputs in the brain, endocrine tissue, the liver, and immune cells (Wuarin and Schibler 1990; Fonjallaz et al 1996; Cho et al 2012; Yu et al 2013; Fang et al 2014; Wang et al 2017; Yeung et al 2018). We demonstrate that NF-κB participates in circadian function in unstimulated cells and that its activation repositions CLOCK/BMAL1 genome-wide to sites colocalized with NF-κB, leading to inhibition of core clock repressors and revealing a mechanism by which immune activation can alter circadian rhythms in mice
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