4.7 Article

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

Journal

GENES & DEVELOPMENT
Volume 32, Issue 21-22, Pages 1367-1379

Publisher

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.319228.118

Keywords

NF-kappa B; circadian; genomics; high-fat diet; inducible transcription; inflammation

Funding

  1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK090625, R01D K100814]
  2. National Institute on Aging (NIA) [P01AG0 11412]
  3. Chicago Biomedical Consortium [S-007]
  4. NIDDK [R01 DK108987]
  5. National Institute of Child Health and Human Development (NICHD) [R01 HD089552]
  6. American Diabetes Association (ADA) [1-17-IBS-137]
  7. Alfediam grant
  8. EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD089552] Funding Source: NIH RePORTER
  9. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020595, R01DK100814, R01DK108987, R01DK090625] Funding Source: NIH RePORTER
  10. NATIONAL INSTITUTE ON AGING [P01AG011412] Funding Source: NIH RePORTER

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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-kappa B 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-kappa B relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-kappa B, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-kappa B during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-kappa B in both unstimulated and activated conditions. Together, these data highlight NF-kappa B-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.

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