NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1

In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory...

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Bibliographic Details
Published in:PLoS genetics 2021-11, Vol.17 (11), p.e1009933-e1009933
Main Authors: Shen, Yang, Endale, Mehari, Wang, Wei, Morris, Andrew R, Francey, Lauren J, Harold, Rachel L, Hammers, David W, Huo, Zhiguang, Partch, Carrie L, Hogenesch, John B, Wu, Zhao-Hui, Liu, Andrew C
Format: Article
Language:English
Subjects:
Animals
ARNTL Transcription Factors - genetics
Biology and Life Sciences
Bioluminescence
BMAL1 protein
Calcium-Binding Proteins - genetics
Cell Line, Tumor
Chromatin
Circadian Clocks - genetics
Circadian rhythm
Circadian Rhythm - genetics
Circadian rhythms
Clock gene
CLOCK Proteins - genetics
Cryptochromes
Cryptochromes - genetics
Gene expression
Gene Expression Regulation, Developmental - genetics
Humans
Immunoprecipitation
Independent sample
Inflammation
Inflammation - genetics
Inflammation - pathology
Kinases
Locomotor activity
Mammals
NF-kappa B - genetics
NF-κB protein
Phenotypes
Physiology
RelA protein
Research and analysis methods
Suprachiasmatic nucleus
Suprachiasmatic Nucleus - metabolism
Transcription Factor RelA - genetics
Transcription factors
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Summary:In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1009933