Requirement for NF-κB in maintenance of molecular and behavioral circadian rhythms in mice

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.

Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes

“…Current data also suggests that the effects of inflammation on the β-cell circadian clock may extend beyond suppression of core circadian clock genes, but also encompass epigenetic reprogramming toward a distinct circadian transcriptional program as recently demonstrated in lung and liver cells exposed to pro-inflammatory conditions such as endotoxemia, LPS, and high fat diet 29,40,41 . For example, lung endotoxemia led to an emergence of circadian rhythms in genes enriched for key pro-inflammatory signaling pathways 29 .…”

“…Recent reports demonstrate that the effects of cellular inflammatory stress may extend to reprogramming of BMAL1:CLOCK genomic binding toward a distinct circadian transcriptional program 29,40,41 . Therefore, we next set out to determine whether exposure to IL-1β also alters genome-wide DNA binding patterns of BMAL1 and CLOCK in β-cells.…”

“…For example, lung endotoxemia led to an emergence of circadian rhythms in genes enriched for key pro-inflammatory signaling pathways 29 . Moreover, in hepatocytes, activation of pro-inflammatory NF-κB signaling resulted in relocalization of BMAL1 genomic sites during LPS-induced inflammation towards genes involved in immune, apoptotic, and metabolic programs 40 . This effect was shown to be dependent on p65 expression and enhanced chromatin accessibility, providing a plausible explanation for the emergence of BMAL1:CLOCK novel binding sites in response to inflammation 40 .…”

“…Moreover, in hepatocytes, activation of pro-inflammatory NF-κB signaling resulted in relocalization of BMAL1 genomic sites during LPS-induced inflammation towards genes involved in immune, apoptotic, and metabolic programs 40 . This effect was shown to be dependent on p65 expression and enhanced chromatin accessibility, providing a plausible explanation for the emergence of BMAL1:CLOCK novel binding sites in response to inflammation 40 . Additionally, BMAL1:CLOCK has been recently shown to function as a pioneer transcription factor thereby regulating DNA accessibility of numerous tissue-specific and ubiquitous transcription factors through nucleosome removal and chromatin modification 4 .…”

Neurogenetic basis for circadian regulation of metabolism by the hypothalamus

“…Similarly, REV-ERBα has been shown to mediate transcriptional rhythms through long-range enhancer-promoter looping (Kim et al 2018). Diet can also remodel circadian behavioral and transcriptional rhythms (Kohsaka et al 2007;Eckel-Mahan et al 2013), in part through interaction with tissue-specific metabolic and inflammatory TFs such as p65, SREPB, and PPARα (Guan et al 2018;Hong et al 2018). While transcriptomic analyses have provided insight into the role of clock cycles in peripheral tissue physiology, interrogation of circadian transcriptional mechanisms at the level of chromatin organization and long-range contacts within neurons remains incomplete.…”