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

ABSTRACT: Purpose: In this study we employed unbiased, genome-wide techniques to investigate how inflammation-induced NF-kB activation by acute (LPS vs. saline) and chronic (high-fat diet vs. regular chow) environmental stimuli leads to circadian disruption. Methods: We performed ChIP-seq with antibodies directed against the p65 subunit of NF-kB, CLOCK, BMAL1, H3K27Ac and RNA Poll II in livers from mice treated with LPS or saline. ChIP-seq analysis was also performed in livers from mice that were fed high-fat diet for 4 weeks or regular chow. In addition, we performed ChIP-seq with BMAL1 in mouse embryonic fibroblast deficient in p65. Results: Induction of NF-kB reconfigures the genome-wide position of core clock transcription factors. Acute (i.e. LPS) and chronic (e.g. high-fat diet) inflammation-induced NF-kB re-localizes components of the forward limb of clock (CLOCK/BMAL1) to sites convergent with NF-kB and acetylated H3K27 and enriched in RNA POL II in liver. In addition, NF-kB activation leads to higher p65 binding specific to E-box elements within the negative limb of the clock with both acute and chronic stimuli. Conclusions: Our findings cast new light on NF-kB as a pivotal genomic control node integrating metabolic inflammation and circadian systems at both the cellular and organismal levels. In particular, NF-kB directly regulates the expression of the negative limb of the clock while at the same time the clock activator TFs CLOCK/BMAL1 co-localize with NF-kB at new sites to regulate transcription following inflammatory stimuli. In addition, our data indicate significant overlap between NF-kB activation following both acute and chronic inflammatory challenges in liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE117488 | GEO | 2018/11/20

REPOSITORIES: GEO